TWI794447B - 輸液製劑 - Google Patents
輸液製劑 Download PDFInfo
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- TWI794447B TWI794447B TW108108432A TW108108432A TWI794447B TW I794447 B TWI794447 B TW I794447B TW 108108432 A TW108108432 A TW 108108432A TW 108108432 A TW108108432 A TW 108108432A TW I794447 B TWI794447 B TW I794447B
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Abstract
本發明是以提供一種在長期保存時能抑制二液混合後之不溶性異物的產生之輸液製劑作為課題。
透過本發明,可提供一種輸液製劑,具有以可連通之間隔而隔開的2室,
其中第1室容納有第1室輸液,其含有脂肪乳劑、且進一步含有選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群組中至少一種,且
第2室容納有第2室輸液,其含有胺基酸及至少鈣作為電解質;
前述第1室輸液當中,具緩衝性之胺基酸、與二價之有機酸及三價之有機酸之合計含有比例為0.15g/L~0.5g/L,且
在間隔連通之後48小時之時間點,前述第1室輸液及第2室輸液的混合液之pH值在6.53以下。
Description
發明領域
本發明係有關於一種含有脂肪、胺基酸、及電解質之輸液製劑。更詳細地說,本發明係有關於一種具有2室容器之輸液製劑,且是第1室容納有糖及脂肪乳劑,第2室容納有胺基酸及電解質之輸液製劑。
發明背景
作為用於靜脈營養(PN)之輸液製劑,已提出一種輸液製劑,具有以可連通之間隔而隔開的2室,第1室容納有包含了糖及脂肪乳劑之第1室輸液,且第2室容納有包含了胺基酸及電解質之第2室輸液(經由靜脈營養輸液製劑)(專利文獻1)。
該等輸液製劑是使用於週邊靜脈營養法(PPN)及中央靜脈營養法(TPN)等。
該等輸液製劑在製造後,經流通及販賣而輸送至病院等的使用設施,進一步,直到實際在臨床使用為止的期間,是被保管於該設施之內。該等輸液製劑需要從製造到臨床使用為止的期間中之安定性。通常,能確保安定性之期間是透過試驗來找出,再設定輸液製劑的使用期限使之不會超過該期間,藉此確保輸液製劑之安定性。
先行技術文獻
專利文獻
[專利文獻1]國際公開第2012/073891號
發明概要
發明欲解決之課題
本發明人等透過獨自研討,發現在製造後經過一定期間之經靜脈營養輸液製劑,在間隔連通後的第1室輸液及第2室輸液之混合液當中,會有觀察到不溶性異物之情形。
本發明是以提供一種在長期保存時能抑制二液混合後的不溶性異物之產生的輸液製劑為課題。
用以解決課題之手段
本發明人等透過獨自研討,找出了該不溶性異物在二液混合後產生的原因。根據本發明人等已究明之事項,長期保存時的第1輸液當中會產生游離脂肪酸,當二液混合後會因為該游離脂肪酸之存在而造成不溶性異物生成。根據該見解並反覆嘗試與錯誤,本發明人等發現到第1室輸液若含有0.15g/L以上的選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群組中至少一種,就能抑制長期保存時的第1輸液當中游離脂肪酸的產生。進一步,本發明人等還發現在間隔連通後之第1室輸液及第2室輸液的混合液之pH值若在6.53以下,能抑制二液混合後因為該游離脂肪酸存在而生成不溶性異物。
亦即,本發明是經由反覆改良而完成,包含有分別記載於以下各項之態樣。
[項1] 一種輸液製劑,具有以可連通之間隔而隔開的2室,
其中第1室容納有第1室輸液,其含有脂肪乳劑、且進一步含有選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群組中至少一種,且
第2室容納有第2室輸液,其含有胺基酸及至少鈣作為電解質;
前述第1室輸液當中,具緩衝性之胺基酸、與二價之有機酸及三價之有機酸之合計含有比例為0.15g/L~0.5g/L,且
在間隔連通之後48小時之時間點,前述第1室輸液及第2室輸液的混合液之pH值在6.53以下。
[項2]如項1之輸液製劑,其中前述脂肪乳劑含有乳化劑,且前述第1室輸液含有0.01~2w/v%前述乳化劑。
[項3]如項1或2之輸液製劑,其中間隔連通後的前述第1室輸液及第2室輸液的混合液含有1mEq/L以上的Ca2+
。
[項4]如項1~3中任一項之輸液製劑,其中第2室輸液進一步至少含有檸檬酸作為電解質,且第2室輸液當中,檸檬酸的濃度(mEq)在鈣的濃度(mEq)以上。
[項5]如項1~4中任一項之輸液製劑,其中第1室輸液至少含有組胺酸作為前述具緩衝性之胺基酸。
[項6]一種藉由間隔連通而獲得的如項1~5中任一項之前述第1室輸液及第2室輸液的混合液。
發明效果
本發明之輸液製劑於長期保存時能抑制二液混合後的不溶性異物之產生。因此,能將使用期間設定成更長期間。
用以實施發明之形態
以下對於本發明進行更詳細之說明。
本發明係有關於一種具有以可連通之間隔而隔開的2室之輸液製劑,在第1室容納有包含脂肪乳劑之第1室輸液,在第2室容納有包含胺基酸及電解質之第2室輸液。
第1室輸液
本發明所使用的第1室輸液含有脂肪乳劑,還含有選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群組中至少一種。
摻合於第1室輸液之脂肪乳劑是使用乳化劑將油脂分散於水中而調製成之水中油型乳劑。該脂肪乳劑之調製可依據通常方法進行。例如,於水中加入油脂及乳化劑後,攪拌並調製出粗乳化液,接著將粗乳化液以高壓乳化法等慣用方法進行乳化而調製出。
作為油脂,適合使用食用油。可舉例如植物油(大豆油、橄欖油、棉籽油、紅花子油、玉米油、椰子油、紫蘇油、荏胡麻油等)、魚油(沙丁魚油等)、中鏈脂肪酸三酸甘油酯(碳數8~10之脂肪酸的三酸甘油酯)[商品名︰「Panasate」(日本油脂社製)、「ODO」(日清製油社製)、「COCONARD」(花王社製)、「Miglyol」(Mitsuba貿易社)等]、化學合成三酸甘油酯類[2-亞油醯基-1,3-二辛醯基甘油酯(8L8)、2-亞油醯基-1,3-二癸醯基甘油酯(10L10)等]等。該等可單獨使用1種,亦可將2種以上組合使用。
作為乳化劑,可使用例如製劑學上容許的各種乳化劑。例如卵黃磷脂質(卵黃卵磷脂)、氫化卵黃磷脂質、大豆磷脂質(大豆卵磷脂)、氫化大豆磷脂質等,亦或,非離子性界面活性劑等。該等可單獨使用1種,亦可將2種以上組合使用。
可分別舉出大豆油作為特別適合的油脂、卵黃磷脂質(卵黃卵磷脂)作為特別適合的乳化劑。特別是如果使用卵黃卵磷脂等的卵磷脂,則如後述般亦能成為磷的來源,非常適合。
關於脂肪乳劑之調製所使用的油脂及乳化劑之使用比例,只要是能獲得水中油型脂肪乳劑則無特別限定。使用油脂是以在所獲得的脂肪乳劑中成為0.5~6w/v%左右之方式為佳,較佳是成為1~5w/v%左右之比例。此外,使用乳化劑是以在所獲得的脂肪乳劑中成為0.01~2w/v%左右之方式為佳,較佳是成為0.1~1.5w/v%左右,更佳為0.2~1.5w/v%左右之比例。第1室輸液中乳化劑之摻合比例若在此範圍內,則能與本發明之其他特徵互相加成,能抑制長期保存時游離脂肪酸的產生。藉此,能抑制長期保存時二液混合後的不溶性異物生成。
對於本發明特別適合的脂肪乳劑之製法的一具體例如下。亦即,於水中加入油脂及乳化劑,並加入選自於甘油及葡萄糖之至少1種,其後,攪拌並調製出粗乳化液,接著將以高壓乳化法等慣用方法進行乳化。採用高壓乳化法時,該方法是使用例如Manton Gaulin均質機等乳化機使粗乳化液在20~700Kg/cm2
左右之條件下通過2~50次左右,較佳為通過3~20次左右。此外,該方法中,甘油及/或葡萄糖是在乳化之際存在即可,例如,亦可以是在使用了油脂與乳化劑調製的粗乳化液中添加甘油及/或葡萄糖再進行乳化。獲得之脂肪乳劑是以含有甘油及/或葡萄糖5~70w/v%左右為佳,較佳為含有10~30w/v%左右。
第1室輸液還包含有選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群組中至少一種。第1室輸液當中,具緩衝性之胺基酸、與二價之有機酸及三價之有機酸之合計含有比例為0.15g/L~0.5g/L。在此,具緩衝性之胺基酸的合計含有比例是根據作為游離胺基酸之該等胺基酸的量來計算。雖不拘泥於理論,然根據本發明人等之研討,推論長期保存時生成的游離脂肪酸是從油脂與乳化劑分解生成。還發現該分解生成之程度取決於pH值。此外,可想知伴隨游離脂肪酸生成造成pH降低,因此更促進了游離脂肪酸的生成。從以上事項得知,若欲抑制二液混合後的不溶性異物之生成,可想知重要的是將第1室輸液的pH值保持於最適合範圍內。若欲如此,提高第1室輸液在該最適合範圍內的pH值之緩衝性,是第1室輸液的pH值維持於該最適合範圍內所必要的。能使從油脂與乳化劑分解生成之游離脂肪酸等的產生受到抑制之pH最適合範圍是以4.5~6.5為佳,較佳為5.0~6.5,更佳為5.5~6.5。
作為具緩衝性之胺基酸並無特別限定,只要是能提高第1室輸液在能使從油脂與乳化劑分解生成之游離脂肪酸等的產生受到抑制之pH範圍下的緩衝性,使第1室輸液之pH值控制在該範圍內即可,可舉例如組胺酸、離胺酸及精胺酸等。藉由具緩衝性之胺基酸,能防止從油脂與乳化劑分解生成之游離脂肪酸等的產生,且能抑制第2室輸液的pH值隨時間經過而降低。作為如此具緩衝性之胺基酸,是以L-組胺酸及L-離胺酸為佳,較佳為L-組胺酸,更佳為實質上僅由L-組胺酸構成,或者僅有L-組胺酸。組胺酸亦能作為pH調整劑發揮機能。
作為二價之有機酸及三價之有機酸並無特別限定,只要是能提高第1室輸液在能使從油脂與乳化劑分解生成之游離脂肪酸等的產生受到抑制之pH範圍下的緩衝性,使第1室輸液之pH值控制在該範圍內即可,可舉例如檸檬酸、琥珀酸、蘋果酸及酒石酸等。藉由二價之有機酸及三價之有機酸,能防止從油脂與乳化劑分解生成之游離脂肪酸等的產生,且能抑制第2室輸液的pH值隨時間經過而降低。檸檬酸、琥珀酸、蘋果酸及酒石酸亦能作為pH調整劑發揮機能。
第1室輸液含有以總量計為0.15g/L以上的選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群組中至少一種,藉此能使第1室輸液在長期保存時之游離脂肪酸的產生受到抑制。因此,在長期保存時之二液混合後不溶性異物之產生受到抑制。從該效果之觀點來看,較佳為第1室輸液含有以總量計為0.2g/L以上的選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群組中至少一種。又,第1室輸液當中,選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群組中至少一種的合計含有比例之上限值可例示如0.6g/L,較佳為0.5g/L。第1室輸液當中,若選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群組中至少一種的合計含有比例在此範圍內,從作為醫藥品添加物的使用實績及摻合葡萄糖等還原糖時防止著色之觀點來看,係屬較佳。綜合以上事項,作為第1室輸液當中,選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群組中至少一種的合計含有比例,是以0.15g/L~0.6g/L為佳,較佳為0.2g/L~0.3g/L。
又,還可因應需要而進一步在脂肪乳劑中添加摻合各種已知可添加摻合之添加劑。作為添加劑,可舉例如pH調整劑。作為pH調整劑,可使用在輸液製劑方面屬於周知者,例如鹽酸等的酸或氫氧化鈉、氫氧化鉀等鹼,其他還能使用有機酸或胺基酸。作為有機酸可例示如醋酸及乳酸等。作為胺基酸,可例示如L-離胺酸等。該等當中,油溶性材料可以事先混合在構成乳化液之油性成份中來使用。水溶性材料可以是混合於注射用水,也可以添加調配於獲得的脂肪乳劑之水相中。該等的添加摻合量可作適宜之設定,例如與該等的習知添加摻合量相同即可。
第1室輸液當中脂肪乳劑的摻合比例以油脂量換算,可以是例如0.5~6w/v%,以1~5w/v%為佳,較佳為2~5w/v%。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中之脂肪乳劑量,以油脂量換算,可以是例如0.25~6w/v%、以0.5~3w/v%為佳,較佳為1~2.5w/v%。
第1室輸液之pH值是以4.5~6.5為佳,較佳為5.0~6.5,更佳為5.5~6.5。若在如此pH範圍內,能抑制第1室輸液當中從油脂與乳化劑分解生成之游離脂肪酸等的產生,且有使脂肪乳劑與維生素B1
安定化的預期效果。第1室輸液的pH值調整可使用pH調整劑進行。除了可使用前述L-組胺酸及L-精胺酸、以及蘋果酸、檸檬酸、琥珀酸及酒石酸等作為pH調整劑,還可使用鹽酸、醋酸、乳酸、氫氧化鈉及氫氧化鉀等作為pH調整劑。
又,第1室輸液是以添加糖為理想。作為所添加的糖,可舉出葡萄糖、果糖、麥芽糖等還原糖,與木糖醇、山梨醇、甘油等非還原糖等。該等當中,從管理血糖值等的觀點來看,第1室輸液是以添加還原糖為佳,較佳為添加葡萄糖。該等糖可單獨使用1種,亦或組合2種以上使用。
第1室輸液之糖的摻合比例是以70~150g/L為佳。又,連通間隔而獲得之第1室輸液與第2室輸液之混合液當中,糖的濃度是以50~100g/L為佳,較佳為50~75g/L。
此外,為了預防輸液療法施行中的酸中毒發生,第1室輸液是以添加維生素B1
為理想。作為添加至第1室輸液之維生素B1
,可使用硫胺素氯化物鹽酸鹽、硫胺素硝酸鹽、丙舒硫胺、硫辛酸硫胺等。
第1室輸液當中維生素B1
的摻合比例以硫胺素量換算,可以是例如1.5~10mg/L,又以2~8mg/L為佳。又,關於本發明之輸液製劑,連通間隔而獲得的第1室輸液與第2室輸液的混合液當中維生素B1
的濃度,以硫胺素量換算,較佳為1~6mg/L,更佳為1.5~4mg/L。
又,從進一步提昇維生素B1
的安定性之觀點來看,第1室輸液的滴定酸度是以設為10以下為佳。在此,滴定酸度是指將溶液100mL中和至pH7.4為止所需要的0.1mol/L氫氧化鈉溶液之mL量值。
作為第1室輸液之溶劑,通常可使用注射用蒸餾水。
本發明之輸液製劑當中,關於第1室輸液之液量,可因應該輸液製劑之總液量或第2室輸液之液量等作適宜設定。
第1室輸液可以實質上不含鉀。所謂實質上不含鉀,意指沒有添加含鉀的化合物。又,第1室輸液是以實質上不含鈣為佳。所謂實質上不含鈣,意指沒有添加含鈣的化合物。
第1室輸液的滲透壓比為2.0~4.0,較佳為2.0~3.5左右。此處之滲透壓比是指相對於生理食鹽水之滲透壓的比(亦即,將生理食鹽水之滲透壓視作1時的相對比)。在此,輸液的滲透壓比在沒有特別聲明時,是指相對於生理食鹽水之滲透壓的比。
第2室輸液
本發明所使用的第2室輸液含有胺基酸及鈣作為電解質。
作為添加於第2室輸液之胺基酸,只要是以對生體進行營養補給作為目的之胺基酸輸液所使用之物即可。本發明中,胺基酸通常是以游離胺基酸的狀態下使用,然而亦可以是藥學上容許的鹽、酯化物、N-醯衍生物、雙肽之型態。作為添加於第2室輸液之游離胺基酸的具體例,可例示如L-白胺酸、L-異白胺酸、L-纈胺酸、L-離胺酸、L-蘇胺酸、L-色胺酸、L-甲硫胺酸、L-苯丙胺酸、L-半胱胺酸、L-酪胺酸、L-精胺酸、L-組胺酸、L-丙胺酸、L-脯胺酸、L-絲胺酸、甘胺酸、L-天門冬醯胺酸、L-麩胺酸等。又,作為胺基酸的鹽,可具體例示如L-精胺酸鹽酸鹽、L-半胱胺酸鹽酸鹽、L-麩胺酸鹽酸鹽、L-組胺酸鹽酸鹽、L-離胺酸鹽酸鹽等無機酸鹽;L-離胺酸醋酸鹽、L-離胺酸蘋果酸等有機酸鹽等。作為胺基酸的酯化物,可具體例示如L-酪胺酸甲基酯、L-甲硫胺酸甲基酯、L-甲硫胺酸乙基酯等。作為胺基酸的N-醯化物,可具體例示如N-乙醯基-L-半胱胺酸、N-乙醯基-L-色胺酸、N-乙醯基-L-脯胺酸等。作為胺基酸的雙肽,可具體例示如L-酪胺醯基-L-酪胺酸、L-丙胺醯基-L-酪胺酸、L-精胺醯基-L-酪胺酸、L-酪胺醯基-L-精胺酸等。其中特別是L-半胱胺酸,用乙醯基半胱胺酸的型態作添加,從安定性的觀點來看係屬較佳。該等胺基酸可單獨使用1種,然而從營養補給的觀點來看,是以將2種以上組合使用為理想。較佳為例如包含有至少所有的必須胺基酸(亦即,L-白胺酸、L-異白胺酸、L-纈胺酸、L-離胺酸、L-蘇胺酸、L-色胺酸、L-甲硫胺酸、L-苯丙胺酸、L-組胺酸這9種的胺基酸)者。
關於第2室輸液之胺基酸的摻合比例,作為游離胺基酸的總量,是以40~120g/L為佳,較佳為50~100g/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中胺基酸之濃度,作為游離胺基酸的總量,是以10~50g/L為佳,較佳為20~40g/L。
又,添加於第2室輸液之胺基酸的組合及摻合比例之合適例如下。亦即,以游離胺基酸換算,L-白胺酸︰5~15g/L、L-異白胺酸︰3~9g/L、L-纈胺酸︰3~9g/L、L-離胺酸︰3~12g/L、L-蘇胺酸︰1.2~6g/L、L-色胺酸︰0.3~3g/L、L-甲硫胺酸︰0.6~4.8g/L、L-苯丙胺酸︰1.8~9g/L、L-半胱胺酸︰0.1~1.8g/L、L-酪胺酸︰0.06~1.2g/L、L-精胺酸︰3~12g/L、L-組胺酸︰1.2~6g/L、L-丙胺酸︰3~9g/L、L-脯胺酸︰1.2~6g/L、L-絲胺酸︰0.6~4.2g/L、甘胺酸︰1.2~6g/L、L-天門冬醯胺酸︰0.12~1.8g/L、以及L-麩胺酸︰0.12~1.8g/L。
又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中胺基酸濃度之適合例如下。亦即,以游離胺基酸換算,L-白胺酸︰3~9g/L、L-異白胺酸︰1.5~4.5g/L、L-纈胺酸︰1.5~4.5g/L、L-離胺酸︰1.5~5g/L、L-蘇胺酸︰0.6~3g/L、L-色胺酸︰0.15~1.5g/L、L-甲硫胺酸︰0.3~2.4g/L、L-苯丙胺酸︰0.85~4.5g/L、L-半胱胺酸︰0.03~0.9g/L、L-酪胺酸︰0.03~0.6g/L、L-精胺酸︰1.5~5g/L、L-組胺酸︰0.6~3g/L、L-丙胺酸︰1.5~4.5g/L、L-脯胺酸︰0.6~3g/L、L-絲胺酸︰0.3~2.1g/L、甘胺酸︰0.6~3g/L、L-天門冬醯胺酸︰0.06~0.9g/L、以及L-麩胺酸︰0.06~0.9g/L。
添加至第2室輸液的電解質是指被使用於輸液領域的電解質,且是指不屬於添加劑等而是屬於有效成份,具體來說是體液(例如血液、細胞內液)所含有的電解質(體液電解質)。可以說是生理學上重要的電解質。更具體地例示如鉀、鈣、鈉、鎂、磷、鋅、氯等。此外,本發明之輸液製劑中,該等的電解質是以不添加於第1室輸液為佳。特別是鉀,為了避免給予高濃度鉀導致的危險性,2室輸液製劑通常會在兩方的輸液中添加,然而本發明之輸液製劑只在第2室輸液添加。
作為鈣的供給源,可例示如葡萄糖酸鈣、氯化鈣、甘油磷酸鈣、乳酸鈣、泛酸鈣、醋酸鈣等的鈣鹽。又,鈣鹽亦可為水合物型態(例如葡萄糖酸鈣水合物等)。鈣在第2室輸液中的濃度是以1以上為較佳,更佳為以成為6~12mEq/L之方式進行摻合。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中鈣的濃度是1以上,較佳為1以上9mEq/L以下,更佳為3~6mEq/L。
作為鉀的供給源,可例示如氯化鉀、醋酸鉀、檸檬酸鉀、甘油磷酸鉀、硫酸鉀、乳酸鉀等。該等當中,甘油磷酸鉀因為亦可作為磷供給源,故屬較佳。該等鉀供給源亦可為水合物型態。鉀是以使第2室輸液中濃度成為40mEq/L以下(更佳為25~40mEq/L)之方式進行摻合為佳。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中鉀的濃度是以16mEq/L以上為佳,較佳為16~25mEq/L,更佳為16~20mEq/L。
作為鈉的供給源,可例示如氯化鈉、乳酸鈉、醋酸鈉、硫酸鈉、甘油磷酸鈉、檸檬酸鈉、乳酸鈉等的鈉鹽。又,若在本發明之輸液製劑中添加磷、鈣及/或鎂時,為了防止該等產生沈澱,作為鈉供給源(的一部分)是以使用檸檬酸鈉為理想。又,鈉供給源亦可為水合物型態。鈉對於第2室輸液之摻合比例,在第2室輸液當中為例如50~100mEq/L,較佳為40~80mEq/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中鈉的濃度是例如25~50mEq/L,較佳為30~40mEq/L。
作為鎂的供給源,可例示如硫酸鎂、氯化鎂、醋酸鎂等。又,鎂供給源亦可為水合物型態。鎂對於第2室輸液之摻合比例,在第2室輸液當中較佳為1~20mEq/L,更佳為5~15mEq/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中鎂的濃度是以0.5~10mEq/L為佳,更佳為2~6mEq/L。
作為磷供給源,若使用無機鹽則會有產生磷酸鈣與磷酸鎂沈澱之情形,因此以使用例如甘油磷酸鈉、甘油磷酸鉀等有機鹽為佳。又,於第1室使用卵磷脂作為乳化劑之際,該卵磷脂亦成為磷供給源。若僅由來自該卵磷脂的磷就足夠提供必要量的磷時,則不需要在第2室添加磷,因此不會產生磷酸鈣等的沈澱,故屬較佳。磷對於第2室輸液之摻合比例,在第2室輸液當中是例如0~20mmol/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中磷的濃度是以1~20mmol/L為佳,更佳為5~10mmol/L。
作為鋅供給源,可例示如硫酸鋅、氯化鋅等。又,鋅供給源亦可為水合物型態。鋅對於第2室輸液之摻合比例,在第2室輸液當中是例如2.5~15μmol/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中鋅的濃度是以1.5~9μmol/L為佳。
作為氯的供給源,可例示如氯化鈉、氯化鉀、氯化鎂、氯化鈣等。氯對於第2室輸液之摻合比例,在第2室輸液當中是例如50~100mEq/L,較佳為40~80mEq/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中氯的濃度是以25~60mEq/L為佳,較佳為30~40mEq/L。
第2室輸液可因應需要而透過pH調整劑將pH調整成6.0~6.8,較佳為調整成6.2~6.7。作為pH調整劑,可以使用與在第1室輸液所記載者相同之物。第2室輸液若滿足上述pH範圍,能對於L-半胱胺酸、L-麩胺酸等容易發生化學變化的胺基酸之安定化有預期效果,此外還能使與第1室輸液混合後的混合液之pH值維持在後述最適合範圍。
又,第2室輸液透過添加選自於由檸檬酸、蘋果酸及琥珀酸所構成之群組中至少一種的2元酸及/或3元酸,藉此能使當甘油磷酸的不純物或分解物亦即磷酸在生成之際,磷酸鈣的析出受到抑制。作為2元酸或3元酸,特別以檸檬酸為佳。第2室輸液所含的2元酸及3元酸的合計濃度(mEq)是在鈣的濃度(mEq)以上為佳。
關於第2室輸液的溶劑,通常亦可使用注射用蒸餾水。
本發明之輸液製劑當中,第2室輸液之滲透壓比是2.0~3.5左右,較佳為2.0~3.0左右。
又,本發明之輸液製劑可因應需要而添加安定化劑。作為添加至本發明之輸液製劑的安定化劑,可例示如亞硫酸氫鈉等的亞硫酸鹽。為了避免第1室輸液所含的維生素B1
分解,亞硫酸鹽會添加於第2室輸液。第2室輸液中亞硫酸鹽的添加量是例如20~100mg/L。
本發明之輸液製劑除了維生素B1
以外還能添加多種維生素。不需要做成3室或4室輸液製劑,能在2室輸液製劑安定地添加多種維生素,這點也是本發明之輸液製劑的特徵之一。維生素有水溶性維生素與脂溶性維生素。以本發明之輸液製劑來說,脂溶性維生素會添加至第1室輸液。又,水溶性維生素可以添加至第1室輸液、第2室輸液之任一者。但如前所述,維生素B1
會添加至第1室輸液。
添加至本發明之輸液製劑的水溶性維生素可舉出維生素B群、維生素C。作為維生素B群,除了維生素B1
(硫胺素),還可舉出維生素B2
(核黃素)、維生素B3
(菸鹼酸)、維生素B5
(泛酸)、維生素B6
、維生素B7
(生物素)、維生素B9
(葉酸)、維生素B12
(氰鈷胺)等。又,作為脂溶性維生素,可舉出維生素A、維生素D(特別是膽鈣化醇)、維生素E、維生素K等。
若要添加維生素C(抗壞血酸),可以添加至第1室輸液、第2室輸液之任一者或兩者,較佳為添加至第2室輸液。若維生素C添加至第2室輸液時,第2室輸液當中維生素C的摻合比例是例如50~500mg/L,較佳為100~400mg/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中,維生素C的濃度是例如25~250mg/L,較佳為50~200mg/L,更佳為40~100mg/L。
作為維生素B2
,可使用核黃素、核黃素磷酸酯鈉、黃素單核苷酸等。添加維生素B2
時,可以添加至第1室輸液、第2室輸液之任一者或兩者。但為了防止維生素B2
與葉酸反應導致葉酸的不安定化,因此較佳作法是將該等分別容納。
例如,若葉酸添加至第1室輸液,則維生素B2
是以添加至第2室輸液為理想。若維生素B2
添加至第2室輸液,第2室輸液當中維生素B2
的摻合比例,以核黃素來說,是例如2.5~15mg/L,較佳為4~8mg/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中,維生素B2
的濃度,以核黃素來說,是例如0.5~10mg/L,較佳為0.5~3mg/L。
作為維生素B6
,可使用吡哆醇、吡哆醇鹽酸鹽等吡哆醇之鹽等。添加維生素B6
時,可以添加至第1室輸液、第2室輸液之任一者或兩者,當維生素B6
與維生素B2
共存時會變成對光非常不安定,因此以添加至與維生素B2
相異之處為理想。
維生素B6
添加至第1室輸液時,第1室輸液當中維生素B6
的摻合比例,以吡哆醇來說,是例如2~10mg/L,較佳為2.5~6mg/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中,維生素B6
的濃度,以吡哆醇來說,是例如1~10mg/L,較佳為1.5~4.5mg/L。
添加葉酸時,可以添加至第1室輸液、第2室輸液之任一者或兩者,以添加至第1室輸液為理想。葉酸添加至第1室輸液時,第1室輸液當中葉酸的摻合比例是例如0.1~0.8mg/L,較佳為0.2~0.6mg/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中葉酸的濃度,是例如0.1~0.7mg/L,較佳為0.2~0.4mg/L。
作為維生素B12
,可使用氰鈷胺、醋酸羥鈷胺、甲基鈷胺等。添加維生素B12
時,可以添加至第1室輸液、第2室輸液之任一者或兩者,然而當第2室添加亞硫酸鹽時,是以添加至第1室輸液為理想。添加維生素B12
至第1室輸液時,第1室輸液當中維生素B12
的摻合比例是例如2~10μg/L,較佳為2.5~6μg/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中,維生素B12
的濃度,是例如0.5~10mg/L,較佳為0.5~3mg/L。
作為菸鹼酸,可使用例如菸鹼醯胺較為合適。添加菸鹼酸時,可以添加至第1室輸液、第2室輸液之任一者或兩者,然而是以添加至第2室輸液為佳。菸鹼酸添加至第2室輸液時,第2室輸液當中菸鹼酸的摻合比例是例如10~100mg/L,較佳為20~50mg/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中,菸鹼酸的濃度是例如5~50mg/L,較佳為5~25mg/L。
作為泛酸,可使用泛醇較為合適。添加泛酸時,可以添加至第1室輸液、第2室輸液之任一者或兩者。泛酸添加至第1室或第2室輸液時,泛酸的摻合比例,以泛醇來說,是例如5~30mg/L,較佳為10~20mg/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中,泛醇的濃度是例如2.5~15mg/L,較佳為5~10mg/L。
添加生物素時,可以添加至第1室輸液、第2室輸液之任一者或兩者,然而是以添加至第2室輸液為佳。生物素添加至第2室輸液時,第2室輸液當中生物素的摻合比例是例如10~100μg/L,較佳為20~80μg/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中,生物素的濃度是例如1~50μg/L,較佳為10~40μg/L。
作為維生素A,可使用視網醇棕櫚酸酯較為合適。又,亦可使用將其溶解於油而成的維生素A油。維生素A是脂溶性維生素,會添加至第1室輸液。第1室輸液當中維生素A的摻合比例是例如1000~5000IU/L,較佳為2000~4000IU/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中,維生素A的濃度是例如500~2500IU/L,較佳為1000~2000IU/L。在此,IU是International Unit(國際單位)。亦稱為維生素A單位。
作為維生素D,可使用膽鈣化醇(維生素D3
)較為適合。維生素D是脂溶性維生素,會添加至第1室輸液。第1室輸液當中維生素D的摻合比例是例如2~10μg/L,較佳為2.5~6μg/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中,維生素D的濃度是例如0.5~10μg/L,較佳為0.5~3μg/L。
作為維生素E,可使用生育酚醋酸酯較為適合。維生素E是脂溶性維生素,會添加至第1室輸液。第1室輸液當中維生素E的摻合比例是例如2~50mg/L,較佳為5~20mg/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中,維生素E的濃度是例如1~25mg/L,較佳為2.5~10mg/L。
作為維生素K,可使用葉萘醌(維生素K1
)較為適合。
維生素K是脂溶性維生素,會添加至第1室輸液。第1室輸液當中維生素K的摻合比例是例如50~2500μg/L,較佳為80~2000μg/L。又,關於本發明之輸液製劑,第1室輸液與第2室輸液的混合液當中,維生素K的濃度是例如20~1200μg/L,較佳為30~1000μg/L。
在此,作為第1室輸液組成與第2室輸液組成所含有的有效成份之一較佳例,可例示如以下組成。此外,選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群組中至少一種會另外加入至第1室。
[第1室輸液]
精製大豆油︰10-50g/L
葡萄糖︰70-150g/L
硫胺素氯化物鹽酸鹽︰3-10mg/L
吡哆醇鹽酸鹽︰3-7mg/L
氰鈷胺︰2.5-5μg/L
葉酸︰0.2-0.5mg/L
維生素A油︰2000-4000IU/L
膽鈣化醇︰2.5-5μg/L
生育酚醋酸酯︰5-20mg/L
葉萘醌︰80-2000μg/L
泛醇︰10-20mg/L
[第2室輸液]
L-白胺酸︰5-15g/L
L-異白胺酸︰3-9g/L
L-纈胺酸︰3-9g/L
L-離胺酸鹽酸鹽︰3.5-15g/L
L-蘇胺酸︰1.2-6g/L
L-色胺酸︰0.3-3g/L
L-甲硫胺酸︰0.6-4.8g/L
乙醯基半胱胺酸︰0.13-2.4g/L
L-苯丙胺酸︰1.8-9g/L
L-酪胺酸︰0.06-1.2g/L
L-精胺酸︰3-12g/L
L-組胺酸︰1.2-6g/L
L-丙胺酸︰3-9g/L
L-脯胺酸︰1.2-6g/L
L-絲胺酸︰0.6-4.2g/L
甘胺酸︰1.2-6g/L
L-天門冬醯胺酸︰0.12-1.8g/L
L-麩胺酸︰0.12-1.8g/L
鈉︰40-80mEq/L
鉀︰25-40mEq/L
鈣︰6-12mEq/L
鎂︰5-15mEq/L
氯︰40-80mEq/L
磷︰0-20mmoL/L
鋅︰2.5-15μmol/L
核黃素磷酸酯鈉︰5-10mg/L
抗壞血酸︰0.1-0.4g/L
生物素︰20-80μg/L
菸鹼醯胺︰20-50mg/L
另外,第1室輸液及第2室輸液兩者都能沿用周知的輸液製造方法來製造。例如,可將上述各輸液成份溶解於注射用蒸餾水並製造。脂溶性成份是以例如上述在乳化時使用為理想。
第1室輸液及第2室輸液的混合液
本發明之輸液製劑在使用時,會將第1室輸液及第2室輸液混合使用。第1室輸液及第2室輸液的混合液之pH值在6.53以下,較佳為在6.4以下。混合液之pH若在此範圍內,會與本發明之其他特徵互相加成,使得長期保存時在二液混合後的不溶性異物之產生受到抑制。具體而言,首先因為本發明之其他特徵,使得長期保存時在第1輸液當中游離脂肪酸的產生受到抑制。此外,藉由將混合液之pH值設於此範圍內,能使起因於游離脂肪酸之混合液中不溶性異物的產生受到抑制。
如此,最終若欲抑制不溶性異物的生成,重點在於將本發明之其他特徵,特別是第1室輸液包含有組胺酸等選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群組中至少一種且以總量計為0.15g/L以上之特徵,以及混合液之pH值在6.53以下之特徵,進行有效的組合。在這個意義上,只要第1室輸液包含有選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群中至少一種且以總量計為0.15g/L以上,且混合液之pH值在6.53以下即可,較佳為(1)第1室輸液包含有選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群組中至少一種且以總量計為0.3g/L以上,且混合液之pH值在6.53以下,亦或(2)第1室輸液包含有選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群組中至少一種且以總量計為0.2g/L以上,且混合液之pH值在6.4以下。
本發明人等發現到起因於游離脂肪酸之混合液中不溶性異物的產生,具體來說是游離脂肪酸與Ca2+
形成鹽而造成的。因此,混合液最終若欲抑制不溶性異物的生成,是以降低第1室輸液及第2室輸液的混合液當中Ca2+
的含有比例為理想,而第1室輸液及第2室輸液的混合液當中Ca2+
的含有比例較佳是以3~6mEq/L為理想。
本發明之輸液製劑的滴定酸度是以1~10為佳,滲透壓比是以2~3為佳。
又,本發明之輸液製劑當中,關於第1室輸液與第2室輸液的體積比,可因應前述第1室輸液與第2室輸液的液量等來作適合的設定,從所含有的各成份之安定性及各室滲透壓的設定之觀點來看,可舉例如(第1室輸液︰第2室輸液)的體積比為(3︰2~3︰5)的體積比。
又,該混合液之熱量是以450~750kcal/L為佳,較佳為500~650kcal/L。該熱量當中,脂肪所佔比例是以40%以下為佳,較佳為20~40%。又,該熱量當中,糖、脂肪、及胺基酸所佔比例是以糖︰40~60%、脂肪︰20~40%、胺基酸︰10~30%為佳,較佳為糖︰45~55%、脂肪︰25~35%、胺基酸︰15~25%。
在此,概略的熱量可以用相對於各成份的添加量(g),以糖為4、脂肪為9、胺基酸為4,分別相乘而獲得。亦即,糖1g的熱量為約4kcal,脂質1g的熱量為約9kcal,胺基酸1g的熱量為約4kcal,據此能求出熱量。上述「該混合液之熱量」之記載是立基於透過此計算方式算出的值。
另外,作為該混合液之各成份的組成之較佳1例,可例示如以下組成。
輸液製劑的使用態樣
在經口攝取不足夠且為輕度的低蛋白血症或輕度的低營養狀態或侵襲期之情況,本發明之輸液製劑是以對於手術前後的患者之營養管理作為目的來使用,特別是適合以手術後或消化器疾病等導致經口營養補給有困難的患者(以接受消化器切除手術之患者較為適合)之營養管理為目的作使用。將本發明之輸液製劑在手術後1~14日間,較佳為手術後1~3日間對患者投藥,能使患者的營養狀態保持健全。投藥量及投藥速度可以在考量各患者的症狀及年齡等之後作適合的設定。特別是,本發明之輸液製劑在上述投藥期間能夠只靠該輸液製劑就使患者的營養狀態保持健全。
本發明之輸液製劑是以從末梢靜脈投藥為佳。亦即,本發明之輸液製劑較佳為末梢靜脈投藥用輸液製劑。通常來說,從末梢靜脈給予輸液時,若輸液之滲透壓過高則會有引起血管痛或靜脈炎之虞,然而使用本發明之輸液製劑則無此疑慮,故從末梢靜脈投藥能較佳地發揮本發明之輸液製劑的這個效果。
輸液容器
作為容納第1室輸液及第2室輸液的容器,只要是具有可連通的2室者則無特別限制,可舉例如以易剝離密封元件形成間隔壁者(特開平2-4671號公報、實開平5-5138號公報等)、將容器空間以夾持元件夾住形成間隔壁者(特開昭63-309263號公報等)、於間隔壁設置有可開封的各種連通元件者(特公昭63-20550號公報等)等以可連通的間隔壁隔開的2室容器(輸液袋)。該等當中,間隔壁是以易剝離密封元件(easy peel seal)形成之輸液袋較為適合大量生產,且連通操作也容易,故屬較佳。又,作為上述容器之材質,可舉出慣用於醫療用容器等的各種透氣性塑膠,例如聚乙烯、聚丙烯、聚氯乙烯、交聯乙烯.醋酸乙烯共聚物、乙烯.α-烯烴共聚物、該等各種聚合物的混合物或積層體等的柔軟性塑膠。
第1室輸液及第2室輸液填充、容納於上述容器,可依照常規方法進行,可舉例如將各輸液在非活性氣體之氣體環境下充填至各室之後,以栓塞堵住並加熱滅菌之方法。
在此,加熱滅菌可採用高壓蒸氣滅菌、熱水淋浴滅菌等周知之方法,可因應需要而在二氧化碳、氮氣等非活性氣體之氣體環境中進行。又,本發明之輸液製劑即使在116℃~121℃的溫度下進行高壓蒸氣滅菌時,不會產生不溶性異物。
不僅如此,容納於上述容器之第1室輸液及第2室輸液,為了確實防止變質、氧化等,較佳是將容器與脫氧劑一起用氧氣隔絕性外袋包裝起來。特別是若採用間隔壁是由易剝離密封元件形成之輸液袋作為容器時,該輸液袋是以從易剝離密封元件部份折起並疊合的狀態使其不會因為外部壓力造成間隔壁連通為佳,例如從易剝離密封元件部份對折的狀態下包裝。又,亦可因應需要進行非活性氣體填充包裝等。
作為適合上述包裝之氧氣隔絕性外裝袋的材質,可使用一般泛用的各種材質的薄膜、薄片等。具體例為例如乙烯.乙烯醇共聚物、聚氯化亞乙烯、聚丙烯腈、聚乙烯醇、聚醯胺、聚酯等,或由含有該等之至少1種的材質所構成的薄膜、薄片等。
又,作為脫氧劑,可使用周知的各種物質,例如以氫氧化鐵、氧化鐵、碳化鐵等鐵化合物作為有效成份之物,或使用了低分子酚與活性碳之物。作為其代表性市售品的商品名,可舉出「Ageless」(三菱氣體化學社製)、「Moduran」(日本化藥社製)、「Secur」(日本曹達社製)、「Tamotsu」(王子化工社製)、「KEEPIT」(Dorency社製)等。
實施例
以下將具體地說明本發明,然而本發明並不受下述之例所限制。
輸液製劑之調製
1.第1室輸液1~4之調製
依據表2所示之組成,將精製大豆油、精製卵黃卵磷脂及葡萄糖加入水中並用均質機作粗乳化後,用高壓乳化機(Manton Gaulin)進行精乳化,再加入L-組胺酸及水並將總量調整成300ml。其次,使用鹽酸調整pH值。如此操作獲得的第1室輸液,滲透壓比為2.9,滴定酸度為1。
2.第2室輸液A~D之調製
依據表3所示之組成,將各胺基酸、電解質及安定化劑(亞硫酸氫鈉)溶解於注射用蒸餾水,調製出胺基酸電解質液。其次,使用冰醋酸調整該液之pH值,並調整成為總量250mL,調製出第2室輸液。如此操作獲得的第2室輸液,滲透壓比為2.7。又,第2室輸液之濃度,以檸檬酸計為12.68mEq/L,以鈣計為10.00mEq/L。
3.填充、包裝
由易剝離密封元件隔開各室的聚乙烯製2室容器,分別於下室填充上述獲得之製劑1~4作為第1室輸液、上室填充製劑A~C作為第2室輸液,並進行各室空間部之氮氣替換,在密封之後,溫度設定為116℃、滅菌時間設為26分鐘以進行高壓蒸氣滅菌。其後,將容器從易剝離密封元件處對折疊合,與脫氧劑一起封入氣體隔絕薄膜的外裝袋,獲得輸液製劑。在此,同一種輸液製劑分別作出3個。
關於填充製劑1~4作為第1室輸液、填充製劑A作為第2室輸液而作成的上述輸液製劑,於60℃/75%RH之條件下保存3週,其後,將第1室輸液與第2室輸液混合,分別在混合之後立刻、混合後26小時、及混合後48小時之時間點進行不溶性異物有無生成之確認、以及在混合後48小時的時間點測定pH值。結果表示於表4。
關於填充了L-組胺酸量為0.1g/L之製劑1作為第1室輸液的輸液製劑,從混合後26小時的時間點就確認到容器內側的面有白色不溶性異物之生成。
關於填充製劑1~4作為第1室輸液、填充製劑B作為第2室輸液而作成的上述輸液製劑,於60℃/75%RH之條件下保存3週,其後,將第1室輸液與第2室輸液混合,分別在混合之後立刻、混合後26小時、及混合後48小時之時間點進行不溶性異物有無生成之確認、以及在混合後48小時的時間點測定pH值。結果表示於表5。
關於填充了L-組胺酸量為0.1g/L之製劑1作為第1室輸液的輸液製劑,從混合後26小時的時間點之後,確認到容器內側的面有白色不溶性異物之生成。又,混合後pH值為6.54與6.55且是填充了製劑2及製劑B的輸液製劑的混合液,從混合後26小時的時間點也確認到容器內側的面有白色不溶性異物之生成。
關於填充製劑1~4作為第1室輸液、填充製劑C作為第2室輸液而作成的上述輸液製劑,於60℃/75%RH之條件下保存3週,其後,將第1室輸液與第2室輸液混合,分別在混合之後立刻、混合後26小時、及混合後48小時之時間點進行不溶性異物有無生成之確認、以及在混合後48小時的時間點測定pH值。結果表示於表6。
關於填充了pH值為6.9的製劑C作為第2室輸液的輸液製劑,不論是填充了製劑1~4之任一者作為第1室輸液,皆是在混合後48小時之時間點的pH值超過6.53,又,從混合後26小時的時間點就確認到容器內側的面有白色不溶性異物之生成。
(無)
Claims (6)
- 一種輸液製劑,具有以可連通之間隔而隔開的2室,其中第1室容納有第1室輸液,其含有脂肪乳劑、且進一步含有選自於由具緩衝性之胺基酸、與二價之有機酸及三價之有機酸所構成之群組中的至少一種,且第2室容納有第2室輸液,其含有胺基酸及至少鈣作為電解質;前述第1室輸液當中,具緩衝性之胺基酸、與二價之有機酸及三價之有機酸之合計含有比例為0.15g/L~0.5g/L,且在間隔連通之後48小時之時間點,前述第1室輸液及第2室輸液的混合液之pH值在6.53以下。
- 如請求項1之輸液製劑,其中前述脂肪乳劑含有乳化劑,且前述第1室輸液含有0.01~2w/v%前述乳化劑。
- 如請求項1或2之輸液製劑,其中間隔連通後的前述第1室輸液及第2室輸液的混合液含有1mEq/L以上的Ca2+。
- 如請求項1或2之輸液製劑,其中第2室輸液進一步至少含有檸檬酸作為電解質,且第2室輸液當中,檸檬酸的濃度(mEq)在鈣的濃度(mEq)以上。
- 如請求項1或2之輸液製劑,其中第1室輸液至少含有組胺酸作為前述具緩衝性之胺基酸。
- 一種藉由間隔連通而獲得的如請求項1至5中任一項之前述第1室輸液及第2室輸液的混合液。
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JPH0881360A (ja) * | 1994-07-13 | 1996-03-26 | Wakamoto Pharmaceut Co Ltd | 安定な脂肪乳剤 |
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JP3430965B2 (ja) * | 1999-04-09 | 2003-07-28 | 三菱ウェルファーマ株式会社 | 安定化された脂肪乳剤含有溶液 |
JP2001079064A (ja) * | 1999-09-10 | 2001-03-27 | Welfide Corp | 輸液入り容器 |
JP4148632B2 (ja) * | 2000-05-18 | 2008-09-10 | ニプロ株式会社 | 末梢静脈栄養輸液製剤 |
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US5993863A (en) * | 1993-04-30 | 1999-11-30 | Yoshitomi Pharmaceutical Industries, Ltd. | Alimentative infusion liquids for administration through peripheral vein |
CN103237541A (zh) * | 2010-11-29 | 2013-08-07 | 株式会社大塚制药工场 | 输液制剂 |
TWI597070B (zh) * | 2010-11-29 | 2017-09-01 | 大塚製藥工場股份有限公司 | 輸液製劑 |
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PH12020551438A1 (en) | 2021-09-01 |
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JP6647656B1 (ja) | 2020-02-14 |
WO2019176996A1 (ja) | 2019-09-19 |
EP3766504A1 (en) | 2021-01-20 |
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