TWI590836B - Radiation sterilization-resistant protein composition - Google Patents
Radiation sterilization-resistant protein composition Download PDFInfo
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- TWI590836B TWI590836B TW102116957A TW102116957A TWI590836B TW I590836 B TWI590836 B TW I590836B TW 102116957 A TW102116957 A TW 102116957A TW 102116957 A TW102116957 A TW 102116957A TW I590836 B TWI590836 B TW I590836B
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- TW
- Taiwan
- Prior art keywords
- protein
- cellulose ether
- ether derivative
- sterilization
- composition
- Prior art date
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Description
本發明係關於含特定之胺基酸群及/或纖維素醚衍生物之具有放射線滅菌耐受性之蛋白質組成物。
近年來，天然及合成蛋白質作為藥劑其重要性日益增大。且，使用於醫療用途時，製品必須滅菌。至於滅菌方法，已知有以高壓釜之加熱滅菌、以γ射線或電子束之電離放射線滅菌、以環氧乙烷氣體之氣體滅菌、以過氧化氫進行之電漿滅菌、使用戊二醛製劑之化學滅菌劑及使用過濾器之分離滅菌等。然而，生理活性蛋白質等之蛋白質因利用熱或放射線之滅菌而使活性降低。以環氧乙烷進行之滅菌會有因化學反應而生成副產物之可能性，或有毒性強、殘留氣體對人體等造成不良影響之可能性。利用化學滅菌劑之滅菌會有必須考慮蛋白質對於滅菌劑之耐受性、pH變化、離子強度變化或溫度變化之問題。因此，現狀為製造含有．固定化蛋白質之醫藥品．醫療品時，必須使所有製造製程為無菌之狀態進行製造，而需要相當大的製造成本。
另外，含蛋白質之溶液雖係利用過濾器分離滅菌，但難以適用於含大粒子之組成物、或固體或半固體組成物。
EP0437095號中揭示可藉γ射線照射將與肝素(heparin)或肝素片段複合之中和氧化纖維素產物(nORC)進行滅菌。然而，該文獻中並未揭示使結合有蛋白質之ORC或nORC滅菌。
EP0562864號中揭示含膠原蛋白海綿基質、第二活體吸收性聚合物(例如氧化再生纖維素(ORC)之分散纖維)、及活性劑(例如肽)之複合傷口處置物質。已記載活性劑可包含於基質或活體吸收性聚合物、或者該二者中，且該複合海綿物質可予以包裝後滅菌。
US5730933號揭示在不使生物學活性之肽之生物學活性消失之下以γ射線或電子束照射而滅菌之方法。該方法係包含形成包含生物學活性之肽與明膠等外來蛋白質之混合物，使該混合物冷凍或冷凍乾燥，接著照射該混合物之步驟之技術，且記載外來蛋白質之存在使肽安定化而防止肽之活性下降。
國際公開WO2000/033893號記載治療肽與由氧化再生纖維素、中和氧化再生纖維素及該等之混合物所組成群組選出之多醣之複合體。而且記載以電離放射線滅菌前藉由使肽與有效量之多醣一起進行製劑，藉此即使以電離放射線滅菌亦不會使肽治療劑之生物學活性消失而安定化。
然而，該等文獻並未教示藉由使纖維素醚衍生物或特定胺基酸群共存可抑制以電離放射線滅菌時之蛋白質失
活。
另一方面，特開2011-47089號公報中記載酵素活性優異之含酵素奈米纖維之製造方法。該方法為以靜電紡絲法使含有酵素與溶解於非水溶劑中之聚合物之紡絲液進行紡絲而形成酵素前驅奈米纖維後，賦予水且進行乾燥者。然而，該文獻並未記載將含酵素奈米纖維滅菌。
本發明之目的係提供一種對放射線滅菌具有耐受性之蛋白質組成物。
本發明人等為解決前述課題而積極研究之結果，意外地發現藉由使由甘胺酸、苯丙胺酸及組胺酸所成之混合物，及/或纖維素醚衍生物共存，可提高蛋白質對放射線滅菌之耐受性，因而完成本發明。
亦即，本發明為一種包含甘胺酸、苯丙胺酸與組胺酸所組成之混合物、及/或纖維素醚衍生物作為添加劑之蛋白質組成物。
圖1為顯示本發明之藉由纖維素醚衍生物與特定添加劑之組合產生之蛋白質滅菌耐受性效果(縱軸：凝膠強度相對值(滅菌前：100))。
圖2為顯示本發明之藉由纖維素醚衍生物與特定添加劑之組合產生之滅菌耐受性效果(縱軸：蛋白質凝聚體增
加量(%))。
本發明為一種包含甘胺酸、苯丙胺酸與組胺酸所組成之混合物、及/或纖維素醚衍生物作為添加劑之蛋白質組成物。
本發明中使用之蛋白質並無特別限制，列舉為例如以纖維蛋白原或凝血酶為代表之止血性蛋白質，以天冬醯胺酶(asparaginase)、觸酶(catalase)、超氧化物岐化酶(superoxide dismutase)、解脂酶(lipase)為代表之酵素，以血紅素(hemoglobin)、血清白蛋白(albumen)、低密度脂蛋白質為代表之輸送蛋白質，以肌動蛋白(actin)、肌球蛋白(myosin)為代表之肌肉蛋白質，以抗體、補體為代表之防禦蛋白質，以白喉(diphtheria)毒素、肉毒(botulinum)毒素、蛇毒為代表之毒素蛋白質，以胰島素、增生因子、細胞激素(cytokine)為代表之蛋白質激素，以白蛋白、鐵蛋白(ferritin)為代表之貯藏蛋白質，以膠原蛋白、角蛋白(keratin)為代表之結構蛋白質，以上皮生長因子(epidermal growth factor：EGF)、類胰島素生長因子(Insulin-like growth factor：IGF)、轉化生長因子(Transforming growth factor：TGF)、神經生長因子(Nerve growth factor：NGF)、腦衍生之神經營養因子(Brain-derived neurotrophic factor：BNDF)、血管內皮
細胞增生因子(Vesicular endothelial growth factor：VEGF)、粒細胞聚落刺激因子(Granulocyte-colony stimulating factor：G-CSF)、粒細胞巨噬細胞聚落刺激因子(Granulocyte-macrophage-colony stimulating factor：GM-CSF)；血小板衍生之成長因子(Platelet-derived growth factor：PDGF)、促紅細胞生成素(Erythropoietin：EPO)、促血小板生成素(Thrombopoietin：TPO)、鹼性纖維母細胞增生因子(Basic fibroblast growth factor：bFGF或FGF2)、肝細胞增生因子(Hepatocyte growth factor：HGF)為代表之成長因子。其中較好為止血性蛋白質、酵素、輸送蛋白質、肌肉蛋白質、防禦蛋白質、毒素蛋白質、蛋白質激素、貯藏蛋白質、結構蛋白質及生長因子，尤其以纖維蛋白原較佳。
本發明中使用之蛋白質可為源自動物者亦可為經基因重組技術製造者。若源自動物則以源自人類較佳。且，以基因重組技術製作之蛋白質若為本質之生物活性相同，則亦可為將胺基酸序列置換為另一胺基酸序列而成之改質體。且，亦可使用該等蛋白質經修飾者，及該等之混合物。
另外，本發明中使用之蛋白質除該成分以外，亦可添加藥學上容許之安定劑或添加劑(以下，將其表示為「安定劑等」，而與本發明中與用於賦予放射線滅菌耐受性之蛋白質共存之添加劑有所區別)。此種安定劑等之例為精
胺酸、異白胺酸、穀胺酸、檸檬酸類、氯化鈣、氯化鈉、蛋白酶抑制劑(例如抑肽酶(aprotinin))、白蛋白、界面活性劑、磷脂質、聚乙二醇、透明質酸(hyaluronic acid)鈉、甘油(glycerin)、海藻糖(trehalose)及糖醇(例如甘油(glycerol)、甘露糖醇)等。其中較好為由精胺酸、氯化鈉、海藻糖、甘露糖醇及檸檬酸類選出之1種以上，最好為檸檬酸類。
本發明中使用之蛋白質與安定劑等之混合物中，相對於該混合物100重量份含35重量份以下，較好含30重量份以下之蛋白質。
本發明中使用之添加劑為由甘胺酸、苯丙胺酸及組胺酸所組成之混合物時，相對於添加劑與蛋白質之合計100重量份，甘胺酸通常含有5重量份以上90重量份以下，較好15重量份以上60重量份以下，更好20重量份以上40重量份以下，苯丙胺酸通常含有1重量份以上80重量份以下，較好2重量份以上40重量份以下，更好4重量份以上20重量份以下，組胺酸通常含有2重量份以上70重量份以下，較好5重量份以上40重量份以下，更好8重量份以上20重量份以下。
本發明中之添加劑為纖維素醚衍生物時，本發明中使用之蛋白質或蛋白質與安定劑等之混合物亦可擔持於纖維素醚衍生物上，但較好以於纖維素醚衍生物中含有(此處所謂含有係指蛋白質之至少一部分進入到纖維素醚衍生物內部之狀態)之狀態存在。該情況下，亦可使蛋白質或安
定劑等分子分散於纖維素醚衍生物中而存在，但較好以蛋白質分子或安定劑等分子分別凝聚而成者進一步聚集之粒子(以下有時將包含與安定劑等之混合粒子記載為「蛋白質粒子」)分散存在。
此蛋白質或蛋白質粒子在纖維素醚衍生物中之較佳存在樣態，不僅於添加劑為纖維素醚衍生物，而且為由甘胺酸、苯丙胺酸及組胺酸所成之混合物及纖維素醚衍生物之情況亦相同。
本發明中使用之纖維素醚衍生物之具體例可例示為羥基丙基纖維素、甲基纖維素、羥基乙基纖維素、羥基丙基甲基纖維素及羧基甲基纖維素鈉及該等之混合物。
該等中，較好為由羥基丙基纖維素、羥基乙基纖維素、羥基丙基甲基纖維素及該等之混合物所組成群組選擇，最好為羥基丙基纖維素。
又，本發明中使用之纖維素醚衍生物之分子量並無特別限制，但例如在濃度2%、20℃下進行黏度測定時，選擇顯示1~10000mPa．s，較好2~5000mPa．s，更好2~4000mPa．s之黏度之分子量。
本發明之蛋白質組成物中，在不損及其目的之範圍內，亦可併用其他聚合物或其他化合物。
本發明中使用之纖維素醚衍生物較好為高純度，亦即纖維素醚衍生物中所含之添加劑或可塑劑、殘留觸媒、殘留單體、成形加工或後加工所用之殘留溶劑等之殘留物愈少愈好。尤其是用於醫療時有必要抑制至低於安全性之基
準值。
本發明之蛋白質組成物之形狀包含無定形者而無特別限制，列舉為例如薄膜、纖維、薄片、板狀體、管狀體、線狀體、棒狀體、緩衝材、發泡體、多孔質體等。製造成形品時之成形方法只要不使蛋白質活性降低之方法即無特別限制，可採用例如擠出成形、射出成形、簾流成形、壓縮成型、吹塑成形、真空成形、粉末成形、澆鑄成形、注模等適當之成形方法。其中，本發明之蛋白質組成物適用薄膜及纖維形狀。此處之纖維形狀係指使所得之一根或複數根纖維層合，經織造、編織或以其他手法形成之3次元成形體。具體之纖維形態列舉為例如不織布。另外，以該等為基礎經加工而成之管、網等亦包含於纖維形狀中。
於該等製造時，於薄膜或塑膠纖維之製造亦可採用過去以來採用之任一種方法，可列舉為例如澆鑄(cast)法、電紡絲法、吹塑擠出成形法、T模嘴擠出成形法等擠出成形法，簾流法等。前述成形法亦可由溶液成形法進行，或者亦可由熔融成形法進行，但為防止蛋白質功能降低並使蛋白質或蛋白質粒子容易分散，以溶液成形較佳。
本發明中，以澆鑄法為例說明具有薄膜形狀之蛋白質組成物之製造法。以研缽等粉碎蛋白質之冷凍乾燥粉末製作具有適於對溶劑分散之平均粒徑(通常為0.1~200μm，較好為1~100μm)之蛋白質粒子。將其分散於可溶解纖維素醚衍生物且可與蛋白質粒子形成懸浮液，而可在薄膜製作階段蒸發形成薄膜之一種或複數種適當溶劑(2-丙醇或
乙醇等)中後，溶解纖維素醚衍生物進而視需要之聚乙二醇(macrogol)等可塑劑，使蛋白質粒子分散於纖維素醚衍生物溶液中調製濃液。使用所得濃液以澆鑄法製作薄膜。
本發明中之具有薄膜形狀之蛋白質組成物中，蛋白質或蛋白質粒子相對於纖維素醚衍生物，雖依據蛋白質或纖維素醚衍生物之種類而定，但通常含有100重量%以上，較好含有500重量%以上，更好含有800~950重量%。少於其時，會有無法充分發揮蛋白質功能之情況，多於其時會有薄膜之成形性變得不良之情況。
本發明中，具有薄膜形狀之蛋白質組成物之薄膜平均厚度(厚度)雖依用途而定，但較好為10~1000μm。
本發明中，具有纖維形狀之蛋白質組成物之平均纖維徑為例如0.01~50μm，但只要為熟悉本技藝者則可依據使用目的適當設定。另外，亦可為由長纖維所成者。所謂長纖維具體而言係指由紡絲至加工為纖維成形體之步驟中，未施加切斷纖維之步驟所形成之纖維，可藉電紡絲法、紡黏法、熔融吹塑法等形成，但基於可不加熱形成，可抑制蛋白質功能降低方面而言較好使用電紡絲法。
電紡絲法係藉由對溶解有聚合物之溶液施加高電壓，而於電極上獲得纖維成形體之方法。作為步驟則包含製造溶解有聚合物之紡絲液之步驟，對該溶液施加高電壓之步驟，噴出該溶液之步驟，自噴出之溶液蒸發溶劑而形成纖維成形體之步驟，作為任意實施之步驟則為使形成之纖維
成形體之電荷消失之步驟，與因電荷消失而累積纖維成形體之步驟。
以下，以電紡絲法為例，說明本發明中，具有纖維形狀或不織布形狀之蛋白質組成物之製造法。
針對電紡絲法中之製造紡絲液之階段加以說明。本發明中之紡絲液較好使用由纖維素醚衍生物溶液與蛋白質粒子所成之懸浮液。
該懸浮液中之纖維素醚衍生物之濃度較好為1~30重量%。纖維素醚衍生物之濃度低於1重量%時，難以形成纖維成形體而欠佳。且高於30重量%時，所得纖維成形體之纖維徑變大，且懸浮液黏度變高故不佳。更好懸浮液中之纖維素醚衍生物濃度為1.5~20重量%。
纖維素醚衍生物之溶劑只要是可溶解纖維素醚衍生物，且可與蛋白質粒子形成懸浮液，並在紡絲階段蒸發，而形成纖維者即無特別限制，且可單獨使用一種亦可組合複數種溶劑。列舉為例如氯仿、2-丙醇、甲苯、苯、苄基醇、二氯甲烷、四氯化碳、環己烷、環己酮、三氯乙烷、甲基乙基酮、乙酸乙酯、丙酮、乙醇、甲醇、四氫呋喃、1,4-二噁烷、1-丙醇、苯酚、吡啶、乙酸、甲酸、六氟-2-丙醇、六氟丙酮、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、乙腈、N-甲基-2-吡咯烷酮、N-甲基嗎啉-N-氧化物、1,3-二氧雜環戊烷、水、及該等溶劑之混合溶劑。該等中，就作業性或物性等而言，較好使用2-丙醇、乙醇。
混合纖維素醚衍生物溶液與蛋白質粒子，調製懸浮液
之方法並無特別限制，可使用超音波或各種攪拌方法。至於攪拌方法亦可使用如均質機之高速攪拌或磨碎機、球磨機等攪拌方法。其中較好為利用超音波處理之分散方法。
且，亦可於以溶劑與蛋白質粒子形成懸浮液後，添加纖維素醚衍生物調製紡絲液。
且，在調製懸浮液前亦可微細處理蛋白質粒子。至於微細處理有乾式粉碎與濕式粉碎，本發明中可採用任一種方法，亦可組合二者。
至於乾式粉碎處理列舉為使用球磨機之處理、使用行星式研磨機或振動研磨機之處理、使用研缽利用研搗棒搗碎之處理、溶劑攪拌型粉碎機、噴射研磨機、使用石臼之搗碎處理等。
另一方面，作為濕式粉碎處理列舉為在使蛋白質粒子分散於適當分散介質中之狀態下，以高剪切力之攪拌裝置、混練裝置等進行攪拌之處理，或在分散於介質中之狀態下之球磨機、珠粒研磨機處理等。
進而，亦可使用利用噴霧乾燥機製作之蛋白質粒子。
本發明中，具有纖維形狀或不織布形狀之蛋白質組成物中，蛋白質粒子之尺寸並無特別限制，但較好為0.01~100μm之範圍。製作小於0.01μm之蛋白質粉末有技術上困難，大於100μm時則分散性變差，而使纖維成形體變脆弱而不佳。
本發明之蛋白質組成物所用之滅菌方法為放射線滅菌。至於放射線列舉為α射線、β射線、γ射線、中子
束、電子束及X射線。其中以γ射線或電子束較佳，最好為電子束。該等滅菌方法並無特別限制，但放射線之照射量可為10~80kGy，較好為20~30kGy。溫度條件並無特別限制，但可為-80~40℃，較好為-80~30℃。
α射線、正子束(positron)、γ射線、中子束、電子束、X射線等之放射線係與物質碰撞而自構成物質之分子．原子抓取電子。於此時切斷分子鍵，產生反應性高之自由基等，與周邊物質進行2次化學反應。
蛋白質容易因放射線照射而喪失功能(活性)為眾所周知。此認為係因照射使分子鍵切斷，使功能展現根源的「高次結構」遭破壞所引起者。然而，本發明之蛋白質組成物即使經放射線照射仍可抑制其功能降低。此意指保持了本發明組成物中之蛋白質之高次結構，此係蛋白質一般之共通效果。該效果認為係基於所透過之纖維素醚衍生物之厚度而不認為係所謂利用遮蔽所致者，抑制機制並不確定。且，該纖維素醚衍生物之效果藉由添加特定之胺基酸群而顯著提高之現象之機制也不清楚。
本發明之蛋白質組成物亦可進一步含有電子．離子捕捉劑、能量移動劑、自由基捕捉劑、抗氧化劑、可塑劑。電子．離子捕捉劑列舉為N,N’-四甲基苯二胺、二苯二胺、芘、醌等。能量移動劑列舉為苊等。自由基捕捉劑列舉為硫醇、八氫菲、單烷基二苯基醚、生育酚、檸檬酸、丁基化羥基茴香醚、丁基化羥基甲苯、第三丁基氫醌、沒食子酸丙酯、抗化血酸衍生物等。抗氧化劑列舉為BHT、
亞磷酸三酯、酚系抗老化劑、有機硫酸鹽類等。其中較好為使用於食品或醫藥品中一般認為安全之添加劑。添加劑之量並無特別限制，例如相對於蛋白質組成物中之纖維素醚衍生物可含0.01~10重量%之添加劑。
且，滅菌步驟中之含有蛋白質之纖維素醚衍生物較好不含水分。水分率較好為10重量%以下，更好為4重量%以下，又更好為實質上無水者。
另外，本發明之蛋白質組成物亦可包裝於包裝材中進行放射線滅菌。該包裝材料較好使用如鋁之氣體阻隔性高之材料。另外，亦可與脫氧劑或乾燥劑一起密封包裝，亦可於脫氧後充填惰性氣體之狀態包裝，亦可進行該等二者。該脫氧劑及乾燥劑較好為對人體無害，且於放射線滅菌時不失活者。
本發明之蛋白質組成物可使用作為例如要求蛋白質之功能及滅菌性之醫療用材料。
又，本發明中，包含使本發明之蛋白質組成物經放射線滅菌之滅菌蛋白質組成物。
以下，以實施例說明本發明之實施形態，但該等並不限制本發明之範圍。
自利用掃描型電子顯微鏡(KEYENCE股份有限公司：商品名「VE8800」)，以倍率3000倍攝影所得纖維成形體表面獲得之照片隨機選出20個位置測定纖維徑，求得所有纖維徑之平均值作為平均纖維徑。n=20。
將切割成50mm×100mm尺寸之纖維成形體，使用高精度數位測量機(MitsuToyo股份有限公司：商品名「LITEMATIC VL-50」)，以測定力0.01N，以n=15測定纖維成形體膜厚且算出平均值。又，本測定中係以測定設備可使用之最小測定力進行測定。
以10μg/mL將抗人類纖維蛋白原抗體(DAKO A0080)固定化於ELISA盤(NUNC 468667)上。以含0.05%Tween20之PBS洗淨後，於各孔中添加BLOCK ACE(西方墨點阻斷劑)(DS Pharma Bio Medical UK-B80)，且進行遮蔽。以含0.05%Tween20之PBS洗淨後，添加檢體。使用人類纖維蛋白原(Enzyme Research Laboratories No.FIB3)作為標準品，作成校正曲線。以含0.05%Tween20之PBS洗淨後，添加HRP標識抗人類纖維蛋白原抗體(CPL 5523)，反應後，以含0.05%Tween20之PBS洗淨，添加TMB試藥(KPL 50-76-
02 50-65-02)，靜置6分鐘進行顯色。添加1M H3PO4，終止顯色，以微量盤式分析儀(Microplate reader)測定OD450-650nm。
以5μg/mL將抗人類凝血酶抗體(Affinity Biological公司，No.SAHT-AP)固定化於ELISA盤(NUNC 468667)上。以含0.05%Tween20之PBS洗淨後，於各孔中添加BLOCK ACE(DS Pharma Bio Medical UK-B80)，進行遮蔽。以含0.05%Tween20之PBS洗淨後，添加檢體。使用人類凝血酶(Haematologic Technologies公司：HCT-0020)作為標準品，作成校正曲線。以含0.05%Tween20之PBS洗淨後，添加0.1μg/mL之HRP標識抗人類凝血酶抗體(Affinity Biological公司，No.SAHT-HRP)。反應後，以含0.05%Tween20之PBS洗淨，添加TMB試藥(Dako S1599)，靜置10分鐘進行顯色。添加0.5M H2SO4，終止顯色，以微量盤式分析儀測定OD450-650nm。
於BD公司製之聚苯乙烯管中添加試料20μL與80μL之活性測定用稀釋溶液(0.01% F-68，50mmol/L NaCl，50mmol/L Tris-HCl，pH8.4)，在37℃培育3分鐘。將作為標準品之重組凝血酶(JPU凝血酶標準400U/mL或
WHO/US凝血酶標準，110IU/mL：本公司調整品)，以相同之緩衝液，在JPU之情況使用稀釋成4、2、1、0.5、0.25U/mL，在IU之情況使用稀釋成6、3、1.5、0.75、0.375IU/mL而成者。於其反應液中添加100μL之試驗組(test team)發色基質S-2238(1mM：第一化學藥品工業)予以攪拌混合，在37℃反應5分鐘後，添加800μL之0.1M檸檬酸溶液終止反應。將反應液200μL移到96孔盤上，測定OD-405/650。
將纖維蛋白原冷凍乾燥粉末(BOLHEAL(註冊商標，以下同)組織接著用：安瓿1)分散於2-丙醇後，以成為16wt%之方式溶解羥基丙基纖維素(6-10mPa．s和光純藥製)，調製含纖維蛋白原粒子/羥基丙基纖維素=20(以纖維蛋白原計9.2)/100(w/w)之紡絲液。在溫度22℃、濕度26%以下，以電紡絲法進行紡絲，獲得薄片狀之纖維成形體。噴出噴嘴之內徑為0.8mm，電壓為11kV，紡絲液流量為1.2mL/h，自噴出噴嘴至平板之距離為15cm。所得纖維成形體之平均纖維徑為0.86μm，平均厚度為137μm。以20kGy使所得薄片進行電子束滅菌。將經滅菌之薄片切斷成0.5cm×0.5cm，以62.5μL生理食鹽水萃取蛋白質且進行ELISA測定。結果，固定化蛋白質量為0.15mg/cm2。另一方面，針對未經滅菌處理之薄片亦同樣進行ELISA測定之結果，固定化蛋白質量為
0.16mg/cm2。由以上，相對於未滅菌薄片之滅菌薄片之蛋白質回收率為94%。
將纖維蛋白原冷凍乾燥粉末(BOLHEAL組織接著用：安瓿1)分散於2-丙醇後，以成為16wt%之方式溶解羥基丙基纖維素(6-10mPa．s和光純藥製)，調製纖維蛋白原冷凍乾燥粉末/羥基丙基纖維素=40(以纖維蛋白原計18)/100(w/w)之紡絲液。在溫度22℃、濕度26%以下，以電紡絲法進行紡絲，獲得薄片狀之纖維成形體。噴出噴嘴之內徑為0.8mm，電壓為12.5kV，紡絲液流量為1.2mL/h，自噴出噴嘴至平板之距離為15cm。所得纖維成形體之平均纖維徑為0.43μm，平均厚度為152μm。以20kGy使所得薄片進行電子束滅菌。將經滅菌之薄片切斷成0.5cm×0.5cm，以62.5μL生理食鹽水萃取蛋白質進行ELISA測定。結果，固定化蛋白質量為0.27mg/cm2。另一方面，針對未經滅菌處理之薄片亦同樣進行ELISA測定之結果，固定化蛋白質量為0.30mg/cm2。由以上，相對於未滅菌薄片之滅菌薄片之蛋白質回收率為90%。
將纖維蛋白原冷凍乾燥粉末(BOLHEAL組織接著用：安瓶1)分散於2-丙醇後，以成為16wt%之方式溶解羥基丙基纖維素(6-10mPa．s和光純藥製)，調製纖維
蛋白原冷凍乾燥粉末/羥基丙基纖維素=100(以纖維蛋白原計46)/100(w/w)之紡絲液。在溫度22℃、濕度26%以下，以電紡絲法進行紡絲，獲得薄片狀之纖維成形體。噴出噴嘴之內徑為0.8mm，電壓為12.5kV，紡絲液流量為1.2mL/h，自噴出噴嘴至平板之距離為15cm。所得纖維成形體之平均纖維徑為0.35μm，平均厚度為191μm。以20kGy使所得薄片進行電子束滅菌。將經滅菌之薄片切斷成0.5cm×0.5cm，以62.5μL生理食鹽水萃取蛋白質進行ELISA測定。結果，固定化蛋白質量為0.78mg/cm2。另一方面，針對未經滅菌處理之薄片亦同樣進行ELISA測定之結果，固定化蛋白質量為0.76mg/cm2。由以上，相對於未滅菌薄片之滅菌薄片之蛋白質回收率為102%。
以20kGy使纖維蛋白原冷凍乾燥粉末(BOLHEAL組織接著用：安瓿1)進行電子束滅菌。以1mL生理食鹽水萃取蛋白質進行ELISA測定。結果，ELISA測定值為31μg/mL。另一方面，針對未經滅菌處理之纖維蛋白原冷凍乾燥粉末(BOLHEAL)亦同樣進行ELISA測定之結果，ELISA測定值為90μg/mL。由以上，相對於未滅菌薄片之滅菌薄片之蛋白質回收率為34%。
將含凝血酶粒子(使含有重組凝血酶1mg/mL、氯化
鈉、檸檬酸鈉、氯化鈣及甘露糖醇之pH7之水溶液經冷凍乾燥者)分散於2-丙醇後，以成為13重量%之方式溶解羥基丙基纖維素(2.0-2.9mPa．s日本曹達製)，調製含凝血酶粒子/羥基丙基纖維素=100/100(w/w)之濃液。以電紡絲法進行紡絲，獲得薄片狀之纖維成形體。所得纖維成形體之厚度為204μm，單位面積重量為2.08mg/cm2，鬆密度為101mg/cm3。將所得薄片切成直徑1cm，以200μL之生理食鹽水萃取蛋白質進行活性測定。其結果，活性測定值為110.3U/cm2。所得薄片照射30kGy之電子束進行滅菌後，測定凝血酶活性。剛照射電子束後之凝血酶活性，以滅菌前作為100%時，為68.4%之保持率。
對含凝血酶粒子(使含有重組凝血酶1mg/mL、氯化鈉、檸檬酸鈉、氯化鈣及甘露糖醇之pH7之水溶液經冷凍乾燥者)照射30kGy電子束進行滅菌後，測定凝血酶活性。照射前之凝血酶活性為404.73U/安瓿。剛照射電子束後之凝血酶活性，以滅菌前作為100%時，為51.8%之保持率。
將切成適當尺寸之組成物，使用高精度數位測量機(MitsuToyo股份有限公司：商品名「LITEMATIC VL-
50」)，以測定力0.01N，以n=9測定之纖維成形體膜厚算出平均值。又，本測定中係以測定設備可使用之最小測定力進行測定。
解脂酶之活性測定係使用連續螢光儀解脂酶測試套組(Continuous Fluorometric Lipase Test Kit)(PROGEN BIOTECHNIK GMBH製造)。由下式算出活性保持率。活性酵素量係由活性值經濃度換算而算出。
活性保持率(%)={滅菌後之活性酵素量(mg/cm2)/滅菌前之活性酵素量(mg/cm2)}×100
另一方面，β-葡糖苷酶(glucosidase)之活性測定係使用Tokyogreen(註冊商標，以下同)-βGlu(積水醫藥股份有限公司)，利用螢光測定進行。由下式算出活性回收率。固定化酵素理論重量係由饋入之酵素粉末重量%與組成物重量算出。
活性回收率(%)={活性酵素量(mg)/(固定化酵素理論重量(mg))×100
由下式算出活性保持率。
活性保持率(%)={滅菌後之活性回收率(%)/滅菌前之活性回收率(%)}×100
將解脂酶粉末(來自豬胰臟，和光純藥製，以下同)
分散於2-丙醇後，以成為13wt%之方式溶解羥基丙基纖維素(6-10mPa．s和光純藥製)，調製解脂酶粉末/羥基丙基纖維素=50/100(w/w)之紡絲液。在溫度27℃、濕度27%以下，以電紡絲法進行紡絲，獲得薄片狀之纖維成形體。噴出噴嘴之內徑為0.8mm，電壓為18kV，紡絲液流量為1.2mL/h，自噴出噴嘴至平板之距離為16.5cm。所得纖維成形體(10cm×14cm)之平均厚度為168μm。以20kGy使所得纖維成形體進行電子束滅菌。將經滅菌之纖維成形體切斷成1cm×1cm，以套組中所含之解脂酶緩衝液1mL萃取解脂酶，進行活性測定。結果，活性酵素量為0.46mg/cm2。另一方面，針對未經滅菌處理之薄片亦進行相同活性測定之結果，活性酵素量為0.40mg/cm2。由以上，相對於未滅菌之纖維成形體之滅菌纖維成形體活性保持率為115%，可知不因電子束滅菌而失活。
將解脂酶粉末分散於2-丙醇後，以成為13wt%之方式溶解羥基丙基纖維素(6-10mPa．s和光純藥製)，調製解脂酶粉末/羥基丙基纖維素=50/100(w/w)之澆鑄液。使用刮板(YOSHIMITSU製造，YBA-3型)，以塗佈寬度15密耳進行澆鑄，獲得薄片。所得薄片(4cm×6cm)之平均厚度為180μm。以20kGy使所得薄片進行電子束滅菌。將經滅菌之薄片切斷成1cm×1cm後，以套組中所含之解脂酶緩衝液1mL萃取解脂酶，進行活性測定。結果，活性
酵素量為0.69mg/cm2。另一方面，針對未經滅菌處理之薄片亦進行相同活性測定之結果，活性酵素量為0.64mg/cm2。由以上，相對於未滅菌薄片之滅菌薄片活性保持率為108%，可知不因電子束滅菌而失活。
將β-葡糖苷酶粉末(來自杏仁，Oriental酵母工業製，以下同)分散於2-丙醇後，以成為13wt%之方式溶解羥基丙基纖維素(6-10mPa．s和光純藥製造)，調製β-葡萄糖苷酶粉末/羥基丙基纖維素=38/62(w/w)之紡絲液。在溫度27℃、濕度27%以下，以電紡絲法進行紡絲，獲得薄片狀之纖維成形體。噴出噴嘴之內徑為0.9mm，電壓為18kV，紡絲液流量為1.2mL/h，自噴出噴嘴至平板之距離為16.5cm。所得纖維成形體(10cm×10cm)之平均厚度為207μm。將所得纖維成形體切斷成2cm×2cm後，以20kGy進行電子束滅菌。以生理食鹽水1mL，對所得滅菌薄片萃取β-葡萄糖苷酶，以Tokyogreen-βGlu進行活性測定。結果，活性回收率為42%。另一方面，針對未經滅菌處理之薄片亦進行相同活性測定之結果，活性回收率為46%。由以上，相對於未滅菌之纖維成形體之滅菌纖維成形體活性保持率為91%，可知藉由包含於纖維素醚衍生物中可抑制酵素之失活。
以20kGy使解脂酶粉末進行電子束滅菌。將1mL解脂酶緩衝液添加於粉末1mg中進行活性測定。結果，活性值為0.25pmol/mL．min。另一方面，針對未經滅菌處理之解脂酶粉末亦進行相同活性測定之結果，活性值為0.34pmol/mL．min。由上述，相對於未經滅菌粉末之滅菌粉末活性保持率為74%。
以20kGy使β-葡萄糖苷酶粉末進行電子束滅菌。將粉末2mg溶解於1mL生理食鹽水中，以Tokyogreen-βGlu進行活性測定。結果，活性保持率為81%。
對纖維蛋白原冷凍乾燥粉末(含纖維蛋白原粒子)照射電子束時，纖維蛋白原產生變化(凝聚體增加，凝膠強度下降)。為了調查抑制因電子束造成之纖維蛋白原變化之效果(滅菌耐受性效果)，而調製纖維蛋白原之分裝液(bulk liquid)，於5mL之玻璃安瓿中充填1mL後進行冷凍乾燥。冷凍乾燥結束針對一部份之安瓿照射30kGy之電子束，且對各冷凍乾燥品進行滅菌前後之比較。
比較評價係利用以小型桌上試驗機EZTest(島津製作所製)進行之凝膠強度測定及以BioSep-SEC-s4000(Phenomenex公司製造)實施凝聚體含量測定(分析條件：50mM，磷酸緩衝液(pH 7.0)，以0.5M精胺酸鹽
酸鹽作為移動相，以流速1.0ml/min進行畫分，以280nm之波長檢測出目的物質；定量比單體波峰更早檢出之波峰作為凝聚體)。
分析時之檢體(分析用檢體)調製順序為以1mL蒸餾水溶解未滅菌冷凍乾燥品及滅菌冷凍乾燥品之安瓿。使其溶液經離心管15000rpm×5分鐘離心，進行0.45μm之過濾器通液後，作為分析用檢體使用。
由以下方法調查藉由纖維素醚衍生物與特定添加劑之組合產生之蛋白質滅菌耐受性效果。
(方法)使用「纖維素醚衍生物+特定添加劑」組成(以下述表1之No.1~6所示之組成①)及相當於自該等去除纖維素醚衍生物之組成之組成②之纖維蛋白原之分裝液，藉由測定其凝膠強度評價作為纖維蛋白原之功能且比較滅菌前後之強度，調查滅菌耐受性效果。結果示於表2。
組成①(將冷凍乾燥粉末與羥基丙基纖維素懸浮於2-丙醇後薄片化)、組成②(冷凍乾燥粉末)一起以使各試料成為1% Fbg濃度之方式以水溶解後，以10mM精胺酸、270mM氯化鈉、pH8.5之緩衝液稀釋成2mg/mL之濃度。
於2mL聚丙烯管中添加Fibrogammin(240單位/mL)10μL、凝血酶溶液(0.2mg/mL、含100mM氯化
鈣)110μL，經移液後，以不夾帶入氣泡之方式添加2mg/mL之纖維蛋白原溶液900μL，在37℃靜置1小時後，以小型桌上試驗機EZTest(島津製作所製)測定凝膠強度。
為相對於上述組成①不含纖維素醚衍生物(羥基丙基纖維素：HPC)者。
滅菌前設為100時之滅菌後之凝膠強度之值示於表2及圖1。
於組成No.1未見到因纖維素醚衍生物之存在產生之滅菌耐受性提高效果，相對於此，組成No.2~6中見到因纖維素醚衍生物之存在產生之該效果，尤其是組成No.3~6較為顯著。
以與實施例8相同之方法，以下述表3之組成(2種)調查甘胺酸之滅菌耐受性效果。結果示於表4。
因添加甘胺酸而抑制了纖維蛋白原凝聚體含量增加。
以與實施例8相同之方法，調查藉由纖維素醚衍生物與特定添加劑之組合產生之滅菌耐受性效果。
使用作為纖維素醚衍生物之羥基丙基纖維素(HPC)及下述表5之8種組成之纖維蛋白原之分裝溶液。關於下述8種組成共通為1.0%纖維蛋白原、110mM氯化鈉、1.0%甘胺酸、0.2%甘露糖醇。結果示於表6與圖2。
藉由添加纖維素醚衍生物，抑制了蛋白質凝聚體含量增加。另外，因纖維素醚衍生物之存在產生之該含量增加抑制效果在苯丙胺酸與組胺酸共存之組成2~4更顯著。由此，實施例7中於組成No.1未見到因纖維素醚衍生物之存在產生之滅菌耐受性提升效果，相對於此，組成No.3~6見到該效果且為顯著，認為係因為組成No.3~6中藉由使苯丙胺酸及組胺酸與纖維素醚衍生物共存，而具有顯著之蛋白滅菌耐受性效果之故。
本發明之蛋白質組成物具有放射滅菌耐受性。本發明之滅菌組成物可一面滅菌一面保持蛋白質之結構或功能。
本發明之蛋白質組成物係利用在例如要求蛋白質之功能及滅菌性之醫療品製造業中。
Claims (12)
- 一種蛋白質組成物，其含有由甘胺酸、苯丙胺酸與組胺酸所組成之混合物、及/或纖維素醚衍生物作為添加劑。
- 如請求項1之蛋白質組成物，其中添加劑為纖維素醚衍生物，蛋白質係以含於纖維素醚衍生物中之狀態存在。
- 如請求項1之蛋白質組成物，其中添加劑係由甘胺酸、苯丙胺酸與組胺酸所成之混合物。
- 如請求項1之蛋白質組成物，其中添加劑係由甘胺酸、苯丙胺酸及組胺酸所成之混合物，及纖維素醚衍生物，且蛋白質係以含於纖維素醚衍生物中之狀態存在。
- 如請求項1、2、4中任一項之蛋白質組成物，其中纖維素醚衍生物係由羥基丙基纖維素、甲基纖維素、羥基乙基纖維素、羥基丙基甲基纖維素、羧甲基纖維素鈉、及該等之混合物所組成群組選出。
- 如請求項1、2、4中任一項之蛋白質組成物，其中纖維素醚衍生物係由羥基丙基纖維素、羥基乙基纖維素、羥基丙基甲基纖維素、及該等之混合物所組成群組選出。
- 如請求項1、2、4中任一項之蛋白質組成物，其中纖維素醚衍生物為羥基丙基纖維素。
- 如請求項1、2、4中任一項之蛋白質組成物，其中蛋白質係由酵素、輸送蛋白質、肌肉蛋白質、防禦蛋白 質、毒素蛋白質、蛋白激素、貯藏蛋白質、結構蛋白質、成長因子、及該等之混合物所組成群組選出。
- 如請求項1、2、4中任一項之蛋白質組成物，其中蛋白質為纖維蛋白原。
- 如請求項1、2、4中任一項之蛋白質組成物，其為薄膜形狀。
- 如請求項1、2、4中任一項之蛋白質組成物，其為纖維形狀或不織布形狀。
- 如請求項1、2、4中任一項之蛋白質組成物，其係經放射線滅菌。
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Families Citing this family (3)
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| CN107213479B (zh) * | 2017-06-22 | 2018-12-28 | 苏州杰纳生物科技有限公司 | 一种包含过氧化氢酶的组合物及用途 |
| WO2020158833A1 (ja) | 2019-01-31 | 2020-08-06 | セルメディシン株式会社 | 無機塩類タンパク複合医療機器 |
| US20230041240A1 (en) * | 2020-01-30 | 2023-02-09 | Leukocare Ag | Reduction of Adsorption |
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| CA2033046C (en) | 1990-01-12 | 1999-08-03 | Lowell Saferstein | Process for preparing a neutralized oxidized cellulose product and its method of use |
| GB9206509D0 (en) | 1992-03-25 | 1992-05-06 | Jevco Ltd | Heteromorphic sponges containing active agents |
| AU682894B2 (en) * | 1993-10-28 | 1997-10-23 | Institut National De La Recherche Agronomique | Composition based on amino acids intended for the treatment of sepsis or of an attack bringing about an inflammatory reaction, in animals and man |
| JP3648573B2 (ja) * | 1995-03-29 | 2005-05-18 | 第一工業製薬株式会社 | カルボキシメチルセルロースナトリウム塩の溶解方法 |
| US6551794B1 (en) * | 1995-11-09 | 2003-04-22 | E. R. Squibb & Sons, Inc. | Stable biotinylated biomolecule composition |
| US5730933A (en) * | 1996-04-16 | 1998-03-24 | Depuy Orthopaedics, Inc. | Radiation sterilization of biologically active compounds |
| US5968895A (en) * | 1996-12-11 | 1999-10-19 | Praecis Pharmaceuticals, Inc. | Pharmaceutical formulations for sustained drug delivery |
| US6103266A (en) * | 1998-04-22 | 2000-08-15 | Tapolsky; Gilles H. | Pharmaceutical gel preparation applicable to mucosal surfaces and body tissues |
| US6056970A (en) * | 1998-05-07 | 2000-05-02 | Genzyme Corporation | Compositions comprising hemostatic compounds and bioabsorbable polymers |
| WO2000029041A1 (de) * | 1998-11-18 | 2000-05-25 | Aventis Behring Gmbh | Stabilisierte proteinzubereitungen für einen gewebekleber |
| GB2344519B (en) * | 1998-12-07 | 2004-05-19 | Johnson & Johnson Medical Ltd | Sterile therapeutic compositions |
| DE10022092A1 (de) * | 2000-05-08 | 2001-11-15 | Aventis Behring Gmbh | Stabilisiertes Protein-Präparat und Verfahren zu seiner Herstellung |
| US7252799B2 (en) * | 2001-08-31 | 2007-08-07 | Clearant, Inc. | Methods for sterilizing preparations containing albumin |
| US6749851B2 (en) * | 2001-08-31 | 2004-06-15 | Clearant, Inc. | Methods for sterilizing preparations of digestive enzymes |
| WO2003028654A2 (en) * | 2001-10-03 | 2003-04-10 | Woolverton Christopher J | Storage-stable human fibrinogen solutions |
| DE60328909D1 (de) * | 2002-11-20 | 2009-10-01 | Arriva Prometic Inc | Zusammensetzung zur behandlung von ichthyosis unter verwendung von antitrypsin |
| DK1809343T3 (da) * | 2004-10-20 | 2012-11-26 | Ethicon Inc | Forstærket absorberbar hæmostatisk flerlagssårforbinding samt fremstillingsfremgangsmåde |
| GB0505975D0 (en) * | 2005-03-23 | 2005-04-27 | Queen Mary & Westfield College | Novel use of peptide |
| WO2008117746A1 (ja) * | 2007-03-22 | 2008-10-02 | Juridical Foundation The Chemo-Sero-Therapeutic Research Institute | 固体状フィブリノゲン製剤 |
| EP2143440A1 (fr) * | 2008-07-09 | 2010-01-13 | Sanofi Pasteur | Agent stabilisant et composition vaccinale comprenant un ou plusieurs flavivirus vivants atténués |
| JP5555928B2 (ja) | 2009-08-28 | 2014-07-23 | 日本バイリーン株式会社 | 酵素含有ナノファイバーの製造方法、酵素含有ナノファイバー、この酵素含有ナノファイバーを含む不織布及びこの不織布を用いた反応装置 |
| RU2535869C2 (ru) * | 2010-01-28 | 2014-12-20 | Эдванст Бионутришн Корпорейшн | Сухая стекловидная композиция для стабилизации и защиты биологически активного материала и способ ее получения |
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| BR112014028441A2 (pt) | 2017-06-27 |
| RU2678828C2 (ru) | 2019-02-04 |
| EP3366301A1 (en) | 2018-08-29 |
| EP2851083A4 (en) | 2015-05-06 |
| MX2014013723A (es) | 2015-08-10 |
| KR102112375B1 (ko) | 2020-05-18 |
| CA2873655A1 (en) | 2013-11-21 |
| KR20150020539A (ko) | 2015-02-26 |
| CN104271145B (zh) | 2017-01-18 |
| EP2851083B8 (en) | 2018-08-08 |
| AU2013261307B2 (en) | 2017-12-21 |
| BR112014028441B1 (pt) | 2021-04-27 |
| MX355012B (es) | 2018-03-28 |
| HK1204948A1 (zh) | 2015-12-11 |
| JP5872032B2 (ja) | 2016-03-01 |
| WO2013172467A1 (ja) | 2013-11-21 |
| JP2016053063A (ja) | 2016-04-14 |
| IN2014DN09624A (zh) | 2015-07-31 |
| US20150132279A1 (en) | 2015-05-14 |
| JP6317307B2 (ja) | 2018-04-25 |
| CN104271145A (zh) | 2015-01-07 |
| AU2013261307A1 (en) | 2014-12-04 |
| JPWO2013172467A1 (ja) | 2016-01-12 |
| CA2873655C (en) | 2021-04-06 |
| EP2851083B1 (en) | 2018-06-20 |
| TW201350146A (zh) | 2013-12-16 |
| EP2851083A1 (en) | 2015-03-25 |
| RU2014150497A (ru) | 2016-07-10 |
| PL2851083T3 (pl) | 2019-04-30 |
| PT2851083T (pt) | 2018-10-18 |
| DK2851083T3 (en) | 2018-08-27 |
| ES2682024T3 (es) | 2018-09-18 |
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