TWI749451B - 包含ω脂肪酸的醫藥組合物及包含彼之輸液製劑 - Google Patents
包含ω脂肪酸的醫藥組合物及包含彼之輸液製劑 Download PDFInfo
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Abstract
本發明係關於包含Ω-3及Ω-6脂肪酸之醫藥組合物及輸液製劑,且本發明之組合物包含一定重量比之Ω-3及Ω-6脂肪酸,以加強抗發炎及免疫增強效應,且因此對由營養缺乏引起之發炎性疾病及免疫受損疾病展現極佳效果。本發明之輸液製劑不僅展現極佳臨床有效性,且亦顯示顯著改良製劑穩定性之效果。
Description
本發明係關於用於預防或治療發炎性疾病或免疫受損疾病之包含Ω脂肪酸之醫藥組合物,及更特定言之,係關於醫藥組合物及包含彼之輸液製劑,其中該醫藥組合物不僅提供脂質營養素,且亦具有極佳抗發炎及免疫增強效應,且因此具有極佳之預防或治療由營養缺乏引起之發炎性疾病或免疫功能下降之效果。
輸液補充嚴重脫水之人生理必需之電解質或水分,且輸液製劑為一種人工溶液,其可以靜脈內投與以非經腸地提供水分及營養素。特別定言之,消化器官有問題或意識喪失之患者容易陷入營養缺乏狀態,及因此,輸液用作為此類患者提供必需營養素之重要手段。
營養缺乏狀態係指至少一種必需營養素或卡路里缺乏之狀態。若此類營養缺乏狀態持續,則會發生發炎性疾病或由免疫功能下降引起之疾病。為抑制此類疾病之發生,在用於提供營養素之輸液製劑中亦一起包含諸如抗發炎劑及免疫強化劑之藥物。
作為輸液製劑中所包含之營養素,存在碳水化合物、蛋白質、脂肪等,其中少量脂肪提供大量能量(1 g = 9 kcal)。用於全非經腸營養(TPN)以完全經由靜脈提供營養素之輸液製劑包含靜脈內脂質乳液,以防止因過量投與碳水化合物而引起之併發症並提供不可能在人體中合成之必需脂肪酸。
第一種脂質乳液為大豆油,其迄今為止已被商業開發並用於多種產品中。然而,在使用一些大豆油作為脂質乳液之情況下,據報導會發生與免疫功能障礙及肝功能障礙相關聯之副作用。大豆油中所含之亞油酸為花生四烯酸之前體。若血液中亞油酸之濃度增加,則由此產生類二十烷酸,從而影響人體之免疫功能、發炎反應、血管功能、血小板聚集等,及因此引起發展併發症之風險增加。
為克服此類風險,最近之脂質乳液傾向於以衍生自多種物質諸如橄欖油、魚油等之油之混合形式開發。最近受關注之脂質乳液為從水生動物中收集之魚油。作為魚油,存在鯊魚肝油、鱈魚肝油、鯨魚油、烏賊油、鯷魚油等,其包含大量以二十碳五烯酸(EPA)及二十二碳六烯酸(DHA)形式之Ω-3脂肪酸。
為重症監護病房(ICU)之患者選擇靜脈內脂質乳液時,絕對量之Ω脂肪酸及某些多不飽和脂肪酸(PUFA)是重要的。根據歐洲非經腸及腸內營養學會(ESPEN)之指南,建議向ICU患者提供之Ω-3脂肪酸之量應為0.1至0.2 g/kg/d。
在此種背景下,本發明者試圖開發包含Ω脂肪酸之醫藥組合物及輸液製劑,其可減輕由於營養缺乏所致之各種發炎性疾病及免疫疾病,並同時充分提供必需之脂質營養素。
[先前技術參考]
[專利文獻]
(專利文獻1)專利文獻1:韓國專利公開案第2011-0107615號
技術問題
本發明之目標係欲提供一種用於預防或治療發炎性疾病或免疫受損疾病之包含Ω脂肪酸之醫藥組合物。
本發明之另一目標係欲提供一種包含Ω脂肪酸之輸液製劑,其不僅可向缺乏營養之個體提供脂質營養素,且亦可減輕由營養缺乏引起之發炎性疾病或免疫受損疾病。
技術解決方案
此詳細描述於下文中。同時,本發明中揭示之各描述及實施例亦可分別應用於其他描述及其實施例。換言之,本發明中揭示之各種要素之所有組合均落入本發明之範圍內。同樣,亦不能看出為本發明之範圍限於下面描述之具體描述。
在本發明之一個態樣中,提供一種用於預防或治療發炎性疾病及免疫受損疾病之包含Ω-3及Ω-6脂肪酸之醫藥組合物。
本發明之組合物可藉由以Ω脂肪酸中之最佳比例包含Ω-3及Ω-6脂肪酸,對發炎性疾病或免疫受損疾病展現顯著效應。特定言之,該組合物可以1:0.75至1:1.25之重量比,較佳1:1之重量比包含Ω-3及Ω-6。
本發明之組合物中所包含之Ω-3及Ω-6脂肪酸之含量可為47至53 mg/mL,其中特別是Ω-3可以23至27 mg/mL之量包含其中,且Ω-6脂肪酸可以20至30 mg/mL之量包含其中。此種含量可在維持Ω-3及Ω-6脂肪酸之重量比之範圍內適當地調整。
Ω-3為在自脂肪酸之甲基末端算起第三個碳原子上具有雙鍵之一系列脂肪酸,其中有亞麻酸、二十碳五烯酸及二十二碳六烯酸。Ω-3脂肪酸最常見於芥花籽油、亞麻籽油、紫蘇籽油或外來藍色魚中,且Ω-3藉由抑制肝臟中之中性脂肪及VLDL合成來降低血液中之中性脂肪含量。另外,已知Ω-3藉由改變會合成中性脂肪之核受體之表現程度來抑制中性脂肪之合成。
在本發明中,Ω-3可為天然或合成之Ω-3脂肪酸、其醫藥上可接受之鹽及其混合物及例如可為α-亞麻酸(ALA)、二十碳五烯酸(EPA)或二十二碳六烯酸(DHA),但不限於此。
由本發明之組合物提供之Ω-3脂肪酸之每日量可為0.1至0.2 g/kg/天,特別是0.125 g/kg或更高。
在本發明中,Ω-6為在自脂肪酸之甲基末端算起第6個碳原子上具有雙鍵之一系列脂肪酸,其中其大量係包含在雞蛋、乳製品、核桃、堅果、種子、大豆油、紅花油及玉米油中。Ω-6為體內產生皮膚及頭髮並維持膽固醇代謝及生殖功能之重要組分。
本發明之Ω-6可為天然或合成之Ω-6脂肪酸、其醫藥上可接受之鹽及其混合物,且例如可為亞油酸、γ亞麻酸、金盞酸、二十碳二烯酸、二高-γ-亞麻酸、花生四烯酸、二十二碳二烯酸、二十二碳四烯酸、二十二碳五烯酸、二十四碳四烯酸或二十四碳五烯酸,但不限於此。
特定言之,本發明提供用於預防或治療發炎性疾病之包含Ω-3及Ω-6脂肪酸之醫藥組合物。
發炎性疾病可為由營養缺乏引起且其特徵可為感染區域出現疼痛、發紅現象、腫脹、發熱及最終功能喪失。發炎性疾病可為選自由以下組成之群之至少一者:胃炎、腸炎、腎炎、肝炎、慢性阻塞性肺病(COPD)、肺纖維化、腸激躁症候群、發炎疼痛、偏頭痛、頭痛、背痛、纖維肌痛、筋膜病、病毒感染、細菌感染、真菌感染、燒傷、由外科手術或牙科手術造成之傷害、PGE過高症候群、動脈粥樣硬化、痛風、霍奇金氏病(Hodgkin's disease)、胰臟炎、結膜炎、虹膜炎、鞏膜炎、葡萄膜炎及急性及慢性發炎性疾病。
根據本發明之一個實驗實例,已確定具有經調整之Ω-3及Ω-6脂肪酸比例之組合物可藉由顯著抑制IL-1β (亦即,發炎性疾病指數)來有效地用於預防或治療發炎性疾病。
特定言之,本發明提供用於預防或治療免疫受損疾病之包含Ω-3及Ω-6脂肪酸之醫藥組合物。
在本發明中,免疫受損疾病可源於由營養缺乏引起之免疫功能下降,且可為例如選自由以下組成之群之至少一者:哮喘、季節性或常年性鼻炎、過敏性鼻炎、結膜炎、異位性皮膚炎、蕁麻疹、紅細胞溶血、急性腎小球腎炎、流感、慢性疲勞及癌症。
另外,本發明提供用於增強免疫力之包含Ω-3及Ω-6脂肪酸之組合物。
根據本發明之一個實驗實例,已經確定,具有經調整之Ω-3及Ω-6脂肪酸比例之組合物可藉由顯著減少脾臟之重量損失(亦即,關鍵之免疫系統)及恢復血細胞免疫功能指數而有效地用於免疫受損疾病。
就組合物之總重量而言,本發明之醫藥組合物可包含22至30%之Ω-3及Ω-6脂肪酸。
除了Ω-3及Ω-6之外,本發明之醫藥組合物亦可另外包含至少一種類型之用於其投與之醫藥上可接受之載劑。作為醫藥上可接受之載劑,可使用以下:鹽水溶液、無菌水、林格氏溶液、緩衝鹽水、葡萄糖溶液、麥芽糖糊精溶液、甘油及其至少一種組分之組合,及若需要,可向其中添加其他習知添加劑諸如抗氧化劑、緩衝溶液、抑菌劑等。
本發明之醫藥組合物可根據預期方法進行非經腸投與(例如靜脈內、皮下、腹膜內或局部施用),特定言之靜脈內投與,及更特定言之向中央靜脈或外周靜脈內投與。劑量可根據患者之體重、年齡、性別、健康狀況、飲食、投與時間、投與方法、排泄速率、疾病之嚴重程度等在其範圍內進行各種調整。
在將本發明之醫藥組合物調配成可注射溶液之情況下,本發明之醫藥組合物可以製備成溶液或懸浮液,製備方式為使得本發明之組合物與穩定劑或緩衝液一起在水中混合,但是調配方法不限於此。作為使用本發明之醫藥組合物之可注射劑型之一個實例,可將本發明之組合物調配成用於瓶之單位劑型之製劑。
在本發明之醫藥組合物中,其劑量可基於目標個體之體重按照年齡來計算。作為一個較佳之實例,對於成人,醫藥組合物之投與劑量可量為5至10 mL/kg/天之輸液,其對應1至2 g/kg/天之每日攝入脂肪。
另外,本發明之醫藥組合物之醫藥上有效量及有效劑量可根據用於調配醫藥組合物之方法、投與方式、投與時間及/或投與途徑等而變化,且可根據各種因素多樣化,該等因素包括欲藉助投與醫藥組合物所達成之反應之類型及程度,進行投與之個體之類型,諸如個體之年齡、體重、一般健康狀況、疾病症狀或嚴重程度、性別、飲食及排泄,欲在同一時間或不同時間用於對應個體之其他藥物組合物之組分等,以及在醫藥領域眾所周知之其他類似因素,及熟習此項技術者可確定並開處方在預期之治療範圍內之劑量。舉例而言,本發明之醫藥組合物之投與可每天進行一次,但不限於此。本發明之醫藥組合物可作為個別治療劑或與其他治療劑組合投與,且可以與習知治療劑依序或同時投與。考慮到以上所有因素,本發明之醫藥組合物可以使得可以最小量達成最大效果而沒有副作用之量投與,且該量可由熟習本發明所屬技術者輕易地確定。
本發明之醫藥組合物可包含至少一種選自由以下組成之群之油:魚油、大豆油、橄欖油、棉籽油、紅花油、芝麻油、椰子油及玉米油。特定言之,本發明之組合物中所包含之Ω-3及Ω-6脂肪酸可源自至少一種選自由以下組成之群之油:魚油、大豆油、橄欖油、棉籽油、紅花油、芝麻油、椰子油及玉米油。
魚油可藉由混合水產動物油作為提供Ω-3脂肪酸之主要來源而獲得,該等油例如富含脂肪之魚油,諸如鯷科(Engraulidae)、鯵科(Carangidae)、鯡科(Clupeidae)、胡瓜魚科(Osmeridae)、鮭科(Salmonidae)及鯖科(Scombridae)。
該油可另外包含合成油諸如中鏈三酸甘油酯。
特定言之,醫藥組合物可包含基於總100 ml該組合物計3.0 g至5.0 g大豆油、3.5 g至4.5 g中鏈三酸甘油酯、5.0 g至6.0 g橄欖油及6.0 g至7.0 g魚油,且更特定言之可包含基於總100 ml該組合物計4 g大豆油、4 g中鏈三酸甘油酯、5.5 g橄欖油及6.5g魚油,其可在維持Ω-3及Ω-6脂肪酸重量比之範圍內適當調整。
本發明之醫藥組合物可另外包含至少一種選自由乳化劑、滲透調節劑、pH調節劑及抗氧化劑組成之群之添加劑。
乳化劑為形成穩定之油顆粒並維持所形成之顆粒之穩定性之材料,且可為選自由蛋黃卵磷脂、氫化蛋黃卵磷脂、大豆卵磷脂、氫化大豆卵磷脂、油酸鈉等組成之群之至少一者。較佳地,乳化劑可為蛋黃卵磷脂及油酸鈉,其可為基於100 ml用於靜脈內投與之該組合物計0.6至1.8% (w/v)蛋黃卵磷脂及0.01至0.05% (w/v)油酸鈉,但不限於此。
滲透調節劑可為選自由氯化鈉、葡萄糖、D-甘露糖醇、山梨糖醇、海藻糖及甘油組成之群之至少一者,且較佳可為基於100 ml用於靜脈內投與之該組合物計1.7至2.5% (w/v)甘油,但不限於此。
pH調節劑可為選自由氫氧化鈉、鹽酸、磷酸、磷酸鹽及檸檬酸組成之群之至少一者,但不限於此。抗氧化劑可為選自由抗壞血酸、二丁基羥基茴香醚、二丁基羥基甲苯、山梨糖醇及生育酚組成之群之至少一者,但不限於此。
抗氧化劑可為選自由抗壞血酸及其鹽、二丁基羥基茴香醚、二丁基羥基甲苯、山梨糖醇及生育酚組成之群之至少一者,但不限於此。
在本發明之另一態樣中,為達成上述目標,提供包含Ω-3及Ω-6脂肪酸之輸液製劑。
本發明之輸液製劑可包含具有Ω-3及Ω-6脂肪酸之組合物。
本發明之輸液製劑可包含一定比例之Ω-3及Ω-6脂肪酸,及因此不僅可顯示其臨床有效性,諸如抗發炎、減緩免疫力下降,等等,且亦可顯示顯著改良製劑穩定性之效果,諸如減緩由多不飽和脂肪酸引起之脂質過氧化,等等。特定言之,該輸液製劑可以包含1:0.75至1:1.25之重量比,特定言之1:1之重量比之Ω-3與Ω-6。
在輸液製劑中,Ω-3及Ω-6脂肪酸可包含在單一隔室中,且該隔室可另外包含胺基酸、電解質及糖。
另外,輸液製劑可接收在複數個隔室中,該等隔室以可連接方式彼此分隔開,以便在使用時可混合製劑。Ω-3及Ω-6脂肪酸或包含彼之組合物可接收在其中一個隔室中。特定言之,本發明之輸液製劑可接收在被分成第一隔室、第二隔室及第三隔室之隔室中。第一隔室可接收用於提供胺基酸及電解質之第一隔室流體;第二隔室可接收用於提供糖之第二隔室流體;及第三隔室可接收用於提供脂肪之第三隔室流體。
電解質可係指以下意義中之電解質,該電解質係在輸液領域中使用,特定言之包含在體液(例如血液及細胞內液)中之電解質,及更特定言之鈣、磷、鈉、鎂、鉀、鋅、氯等,但不限於此。
鈣可為葡萄糖酸鈣、氯化鈣、甘油磷酸鈣或泛酸鈣;鹽可為無機鹽,包括磷酸鈣及磷酸鎂;或有機鹽,包括甘油磷酸鈉及甘油磷酸鉀;鈉可為氯化鈉、乳酸鈉、乙酸鈉、硫酸鈉、甘油磷酸鈉、檸檬酸鈉或其水合物形式;鎂可為硫酸鎂、氯化鎂或乙酸鎂;鉀可為氯化鉀、乙酸鉀、甘油磷酸鉀、硫酸鉀、乳酸鉀或其水合物形式;鋅可為硫酸鋅、氯化鋅或其水合物形式;氯可為氯化鈉、氯化鉀、氯化鎂或氯化鈣,但不限於此。
特定言之,電解質可為選自由二水合氯化鈣、甘油磷酸鈉、水合乙酸鈉、七水合硫酸鎂、氯化鉀及七水合硫酸鋅組成之群之至少一者。電解質可為72至76 mg二水合氯化鈣、400至440 mg無水甘油磷酸鈉、555至570 mg水合乙酸鈉、245至250 mg七水合硫酸鎂、445至451 mg氯化鉀及2.0至2.6 mg七水合硫酸鋅,且較佳74 mg二水合氯化鈣、418 mg無水甘油磷酸鈉、562 mg水合乙酸鈉、247 mg七水合硫酸鎂、448 mg氯化鉀及2.3 mg七水合硫酸鋅,基於100 mL第一隔室流體計,但不限於此。
胺基酸包括游離胺基酸及胺基酸鹽形式。游離胺基酸形式可為選自由以下組成之群之至少一者:L-丙胺酸、L-精胺酸、甘胺酸、L-組胺酸、L-異白胺酸、L-白胺酸、L-離胺酸、L-甲硫胺酸、L-苯丙胺酸、L-脯胺酸、L-絲胺酸、牛磺酸、L-蘇胺酸、L-色胺酸、L-酪胺酸、L-纈胺酸及L-穀胺酸。胺基酸鹽形式可為選自由無機鹽諸如L-精胺酸鹽酸鹽、L-組胺酸鹽酸鹽、L-離胺酸鹽酸鹽等;L-離胺酸乙酸鹽;及L-離胺酸蘋果酸組成之群之至少一者。
從提供營養之觀點來看,該輸液製劑可包含至少兩種胺基酸,且可有效地包含必需胺基酸,亦即L-精胺酸、L-組胺酸、L-異白胺酸、L-白胺酸、L-離胺酸、L-甲硫胺酸、L-苯丙胺酸、牛磺酸、L-蘇胺酸、L-色胺酸及L-纈胺酸。
特定言之,此類製劑可包含基於100 mL第一隔室流體計2.05至2.10 g L-丙胺酸、1.10至1.20 g L-精胺酸、0.98至1.08 g甘胺酸、0.45至0.50 g L-組胺酸、0.50至0.70 g L-異白胺酸、0.68至0.78 g L-白胺酸、0.715至0.735 g L-離胺酸鹽酸鹽、0.30至0.50 g L-甲硫胺酸、0.50至0.62 g L-苯丙胺酸、0.63至0.73 g L-脯胺酸、0.40至0.60 g L-絲胺酸、0.05至0.15 g牛磺酸、0.37至0.47 g L-蘇胺酸、0.13至0.23 g L-色胺酸、0.03至0.05 g L-酪胺酸及0.53至0.63 g L-纈胺酸,及較佳基於100 mL第一種隔室液流體計2.07 g L-丙胺酸、1.15 g L-精胺酸、1.03 g甘胺酸、0.48 g L-組胺酸、0.60 g L-異白胺酸、0.73 g L-白胺酸、0.725 g L-離胺酸鹽酸鹽、0.40 g L-甲硫胺酸、0.56 g L-苯丙胺酸、0.68 g L-脯胺酸、0.50 g L-絲胺酸、0.10 g牛磺酸、0.42 g L-蘇胺酸、0.18 g L -色胺酸、0.04 g L-酪胺酸及0.58 g L-纈胺酸。
第一隔室流體可另外包含pH調節劑。當第一隔室流體與第二隔室流體及第三隔室流體混合時,pH調節劑包含在其中且因此可以維持最佳pH,足夠穩定以不破壞其中所包含之胺基酸。pH調節劑可選自習知類別。較佳地,可使用乙酸酐。
輸液製劑可包含糖,其可為還原糖諸如葡萄糖、果糖、麥芽糖等,及非還原糖諸如木糖醇、山梨糖醇等,且較佳可為最輕易吸收至體內之葡萄糖。
第二隔室流體可另外包含pH調節劑,且pH調節劑可為鹽酸、磷酸、乙酸、檸檬酸或硫酸。
本發明之輸液製劑可以投與給中心靜脈或外周靜脈。若將輸液製劑投與給中心靜脈,則第二隔室流體可包含基於100 ml該第二隔室流體計46.1至46.3 g一水合葡萄糖,較佳46.2 g其。若將輸液製劑投與給外周靜脈,則第二隔室流體可包含基於100 ml該第二隔室流體計14.2至14.4 g單水合葡萄糖,較佳14.3 g其。
第三隔室流體包含油、乳化劑、滲透調節劑、pH調節劑及抗氧化劑,且為用於靜脈內投與之本發明組合物。
在本發明之輸液製劑中,第三隔室流體(即,用於靜脈內投與之組合物)可單獨使用,或可以使得第一隔室流體及第二隔室流體係混合在一起之方式使用,端視需要輸液投與之個體之狀態而定。
若將用於靜脈內投與之本發明組合物與第一隔室流體及第二隔室流體混合,則其混合比例及總劑量可根據各患者之營養狀態及卡路里需求適當地調整。若將本發明之輸液製劑投與給中心靜脈,則第一隔室流體、第二隔室流體及第三隔室流體之體積比可為2.66:1.59:1.00。若將本發明之輸液製劑投與給外周靜脈,則第一隔室流體、第二隔室流體及第三隔室流體之體積比可為2.24:3.86:1.00。然而,第一隔室流體、第二隔室流體及第三隔室流體之體積比不限於此,且可根據營養卡路里之標準良好地進行各種細分。
本發明之輸液製劑可經由頸靜脈為需要營養提供之患者提供卡路里、胺基酸、必需脂肪酸及Ω-3脂肪酸,因為口服或胃腸營養提供係不可能、不充足或受限的。另外,本發明之輸液製劑可用於管理創傷患者之營養,該等創傷患者經歷主要外科手術諸如癌症、AIDS、缺血性腸病、吸收不良、支氣管阻斷/移除、腸梗阻、嚴重肝功能障礙、嚴重急性胰臟炎等。
本發明提供用於預防或治療發炎性疾病或免疫受損疾病之方法,其包括將包含重量比為1:0.75至1:1.25之Ω-3及Ω-6脂肪酸之組合物投與給需要治療之個體之步驟。
如本文所用,術語̚「需要治療之個體」指包括人類之哺乳動物,且術語「投與」意指藉助任何適當之方法向個體提供預定物質。術語「治療有效量」意指誘導動物或人類顯示由研究者、獸醫、醫生或臨床醫生所考量之生物學或醫學反應之活性組分或醫藥組合物之量,且該量包括用於誘導欲治療之疾病或病症之症狀減輕之其量。熟習此項技術者應知曉,本發明之有效組分之治療有效劑量及投與次數可根據所需效果而變化。
本發明之醫藥組合物可每天一次或以一定時間間隔每天至少兩次進行投與。
本發明提供一種包含重量比為1:0.75至1:1.25之Ω-3及Ω-6脂肪酸之組合物在預防或治療發炎性疾病或免疫受損疾病中之用途。
本發明提供一種包含重量比為1:0.75至1:1.25之Ω-3及Ω-6脂肪酸之組合物在製備用於預防或治療發炎性疾病或免疫受損疾病之醫藥製劑中之用途。
若彼此不矛盾,則在本發明之醫藥組合物、治療方法及用途中所提及之物質適用相同。
有利效應
本發明之醫藥組合物可以一定重量比包含Ω-3及Ω-6脂肪酸,且因此可增強抗發炎及免疫增強效應,且因此可預防或治療由營養缺乏引起之發炎性疾病及免疫受損疾病。另外,本發明之輸液製劑可不僅展現極佳臨床有效性,且亦可顯示顯著改良製劑之穩定性。
本發明之模式
在下文中,本發明之構型及效果將藉由實例更詳細地描述。以下實例係僅出於說明本發明之目的提供,且因此本發明之範圍不限於此。
製備實例 1 :醫藥組合物之製法
根據本發明,實例及比較實例之組合物係藉助以下方法製備。
準備兩個製備用槽,使得一個用作製備水相之槽,及另一個用作製備油相之槽。
將注射用水及滲透調節劑(即甘油)插入混合水相之槽中及隨後混合在一起,然後將純化大豆油、純化橄欖油、中鏈三酸甘油酯、純化魚油、純化蛋黃卵磷脂、油酸鈉及生育酚插入混合油相之槽中及隨後用均質混合器(例如IKA均質器)均勻混合。
根據上述製備方法製備之實例及比較實例之詳細組成示於下表1中。
【表1】
組 分 (g/100ml) | 實例1 | 比較實例1 | 比較實例2 | 比較實例3 | 比較實例4 | 比較實例5 | 比較實例6 |
純化大豆油 | 4.0 | 9.7 | 6.8 | 5.6 | 2.0 | 6.0 | 6.0 |
中鏈三酸甘油酯 | 4.0 | 4.0 | 4.0 | 4.0 | 4.0 | 6.0 | 5.0 |
純化橄欖油 | 5.5 | 4.1 | 4.8 | 5.1 | 5.7 | 5.0 | 5.0 |
純化魚油 | 6.5 | 2.2 | 4.4 | 5.3 | 8.3 | 3.0 | 4.0 |
純化蛋黃卵磷脂 | 1.2 | 1.2 | 1.2 | 1.2 | 1.2 | 1.2 | 1.2 |
油酸鈉 | 0.03 | 0.03 | 0.03 | 0.03 | 0.03 | 0.03 | 0.03 |
甘油 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
生育酚 | 0.0194 | 0.0194 | 0.0194 | 0.0194 | 0.0194 | 0.0194 | 0.0194 |
氫氧化鈉 | 適宜量 | 適宜量 | 適宜量 | 適宜量 | 適宜量 | 適宜量 | 適宜量 |
注射用水 | 適宜量 | 適宜量 | 適宜量 | 適宜量 | 適宜量 | 適宜量 | 適宜量 |
將所得各混合物在一個槽中攪拌以混合預乳液,及隨後在600至1,400巴壓力條件下用高壓均質器(APV-2000,Demark)進行乳化,然後用1N氫氧化鈉調節pH。
中鏈三酸甘油酯、純化大豆油、純化橄欖油及純化魚油中所含之Ω-3、Ω-6及Ω-9脂肪酸各係實務上根據歐洲藥典標準進行測量。中鏈三酸甘油酯、純化大豆油、純化橄欖油及純化魚油之量係根據Ω-3、Ω-6及Ω-9脂肪酸之含量進行調節。
上文製備之實例1及比較實例1至6中之Ω脂肪酸之比例及含量如下表2所示。
【表2】
實例1 | 比較實例1 | 比較實例2 | 比較實例3 | 比較實例4 | 比較實例5 | 比較實例6 | |
Ω-6/-3 之比例 | 1.0 / 1.0 | 4.0 / 1.0 | 2.0 / 1.0 | 1.5 / 1.0 | 0.5/ 1.0 | 2.5 / 1.0 | 2.0 / 1.0 |
Ω-3脂肪酸 (mg/mL) | 25.0 | 13.4 | 19.4 | 21.8 | 30.1 | 14.0 | 17.5 |
Ω-6脂肪酸(mg/mL) | 25.1 | 53.3 | 39.0 | 33.0 | 15.1 | 34.8 | 34.9 |
Ω-9脂肪酸(mg/mL) | 58.8 | 58.6 | 58.6 | 58.7 | 56.9 | 56.9 | 57.8 |
製備實例 2 :輸液製劑之製法
為製備根據本發明之輸液製劑,分別製備第一隔室流體及第二隔室流體及隨後以使得在上述製備實例1中所獲得之實例1之組合物用作第三隔室流體之方式進行混合。
在第一隔室流體中,將以下物質插入注射用水:L-丙胺酸、L-精胺酸、甘胺酸、L-組胺酸、L-異白胺酸、L-白胺酸、L-離胺酸鹽酸鹽、L-甲硫胺酸、L-苯丙胺酸、L-脯胺酸、L-絲胺酸、牛磺酸、L-蘇胺酸、L-色胺酸、L-酪胺酸、L-纈胺酸、二水合氯化鈣、無水甘油磷酸鈉、水合乙酸鈉、七水合硫酸鎂、氯化鉀及七水合硫酸鋅,及隨後完全溶解,然後用乙酸調節pH。
在第二隔室流體中,插入單水合葡萄糖並使其完全溶解,然後用鹽酸調節pH。
將以上獲得之第一隔室流體、第二隔室流體及第三隔室流體填充至輸液用塑膠袋中,將輸液用塑膠袋分成三個隔室。之後,經由充氮將其填充流體上方之空隙密封,隨後將其與脫氧劑一起裝入多層膜之外包裝中,及隨後密封。此後,根據習知已知方法在高壓下對所得產品進行蒸汽滅菌。
根據上述製備方法製備之實例2及3之組合物如下表3所示。
【表3】
分類 | 組分名稱 | 實例2 | 實例3 |
含量(g/100 mL) | |||
第一隔室流體 (胺基酸及電解質) | L-丙胺酸 | 2.07 | 2.07 |
L-精胺酸 | 1.15 | 1.15 | |
甘胺酸 | 1.03 | 1.03 | |
L-組胺酸 | 0.48 | 0.48 | |
L-異白胺酸 | 0.60 | 0.60 | |
L-白胺酸 | 0.73 | 0.73 | |
L-離胺酸鹽酸鹽 | 0.725 | 0.725 | |
L-甲硫胺酸 | 0.40 | 0.40 | |
L-苯丙胺酸 | 0.56 | 0.56 | |
L-脯胺酸 | 0.68 | 0.68 | |
L-絲胺酸 | 0.50 | 0.50 | |
牛磺酸 | 0.10 | 0.10 | |
L-蘇胺酸 | 0.42 | 0.42 | |
L-色胺酸 | 0.18 | 0.18 | |
L-酪胺酸 | 0.04 | 0.04 | |
L-纈胺酸 | 0.58 | 0.58 | |
二水合氯化鈣 | 0.074 | 0.074 | |
甘油磷酸鈉 | 0.418 | 0.418 | |
七水合硫酸鎂 | 0.247 | 0.247 | |
氯化鉀 | 0.448 | 0.448 | |
水合乙酸鈉 | 0.562 | 0.562 | |
七水合硫酸鋅 | 0.0023 | 0.0023 | |
乙酸 (100) | 適宜量 | 適宜量 | |
注射用水 | 適宜量 | 適宜量 | |
第二隔室流體 | 單水合葡萄糖 | 46.20 | 14.30 |
鹽酸 | 適宜量 | 適宜量 | |
注射用水 | 適宜量 | 適宜量 |
實驗實例 1 :根據 Ω 脂肪酸之組成比例評估抗發炎效應
評估發炎細胞激素之抑制能力以評定根據本發明之實例及比較實例之組合物之抗發炎效應。
特定言之,從人類外周血單核細胞(PBMC)分離單核細胞,然後將2×105
個單核細胞插入各孔中,及隨後培養。在16小時後,各孔用20 μl實例及比較實例之組合物處理,及隨後在30分鐘後用脂多醣(LPS)處理,使得其最終濃度可達到1 μg/ml。在24小時後,利用酶聯免疫測定法(ELISA)測定IL-1β之表現程度,其結果示於圖1中。
如圖1中所示,已確認IL-1β表現程度隨著Ω-3脂肪酸比例增加而受到抑制。
實驗實例 2 :根據 Ω 脂肪酸之組成比例評估免疫增強功效 實驗實例 2-1 :測量脾臟重量
評估涉及動物模型之免疫力之脾臟重量變化及免疫細胞變化,以評定根據本發明之實例及比較實例之組合物之免疫增強效應。
特定言之,使用大鼠(七週齡雄性SD大鼠,Hallym Experimental Animals, Inc.)作為動物模型,及隨後以25 mg/kg輸注環磷醯胺(CP)以誘導免疫力之急劇下降,之後,在CP投與後之30分鐘、8小時及24小時內,對各大鼠靜脈內給藥0.4 g實例1及比較實例4及6之各組合物。此後,從動物模型中收集關鍵性免疫系統(亦即脾臟),以判別其體重變化,其結果示於圖2中。
如圖2中所示,已確定經環磷醯胺處理之對照組顯示脾臟重量減少,而經本發明實例1之組合物處理之組顯示脾臟重量增加,以顯著地抑制免疫力下降,因此與比較實例4及6相比為極佳。
實驗實例 2-2 :血細胞指數之測量
在實例2-1之動物模型中測量血細胞指數,以評估根據本發明之實例及比較實例之組合物之免疫增強效應。
特定言之,給大鼠以25 mg/kg給藥環磷醯胺(CP)以誘導免疫力之急劇下降,及隨後給藥實例1及比較實例4及6之組合物。在投與後48小時內,從各大鼠心臟收集血液,及隨後用肝素處理,用自動血液分析儀測量免疫功能相關細胞(亦即,嗜中性粒細胞、嗜酸性粒細胞及淋巴細胞)之數量,使得其結果示於圖3中。
如圖3所示,已確定經本發明之實例1之組合物處理之組顯著增強中性粒細胞、嗜酸性粒細胞及淋巴細胞,該等細胞已由於免疫力下降而減少,因此與具有不同Ω脂肪酸比例之比較實例4及6相比為極佳。
實驗實例 3 :根據 Ω 脂肪酸之組成比例確定血清生化指數變化
根據Ω脂肪酸比例,評估對血清生化指數(亦即乳酸脫氫酶(LDH)及肌酐(CREA))之影響。
特定言之,在CP投與後48小時內,從各大鼠心臟收集血液以從中分離血清,然後用血清生化分析儀測量各血清指數,使得其結果示於圖4中。
如圖4所示,已確定經本發明之實例1之組合物處理之組顯著抑制LDH及CREA。
實驗實例 4 :單次靜脈內投與之毒性測試
為評估根據本發明之用於靜脈內投與之組合物之安全性,將動物模型用其靜脈內注射以評定其安全性。
將實例1之用於靜脈內投與之組合物一次性靜脈內投與至比格犬(雄性,28個月大,約11 kg)中。關於臨床投與劑量(基於成人60 kg),以三倍劑量投與該組合物持續至多八小時。投與後,無動物死亡,及未觀測到體重、臨床症狀存在及血液組成之變化。
實驗實例 5 :對脂質輸液製劑之穩定性測試 1
在加速條件(40℃/RH 75%)下,對上述實例1及比較實例2至6進行一個月穩定性評估。用NICOMP設備測量脂質乳液之粒度。關於按項脂質營養素輸注之標準,適用脂質可注射乳液專論之標準,但詳細設定與脂肪酸氧化引起之降解產物有關的游離脂肪酸及溶血磷脂醯膽鹼(LPC)之標準。乳液之脂質顆粒均勻地形成並保持,而與Ω脂肪酸比例無關。另外,如在下表4中所見,所需穩定性標準係例如藉由不顯示根據Ω脂肪酸比例之脂肪酸氧化指數大差異來滿足。
【表4】
項 | 標準 | 實例1 | 比較實例2 | 比較實例3 | |||
初始 | 1 個月 | 初始 | 1 個月 | 初始 | 1 個月 | ||
pH | 6.0~9.0 | 8.3 | 8.2 | 8.2 | 8.2 | 8.1 | 8.2 |
游離脂肪酸 | ≤8.0 mg/mL | 2.4 | 2.9 | 2.3 | 2.8 | 2.4 | 2.9 |
平均顆粒 | ≤500 nm | 192 | 214 | 180 | 199 | 198 | 205 |
最大顆粒 | ≤1 μm | 0.30 | 0.35 | 0.38 | 0.27 | 0.34 | 0.30 |
分散度 | ≤0.25 | 0.04 | 0.05 | 0.12 | 0.02 | 0.06 | 0.03 |
溶血磷脂醯膽鹼 | ≤2 mg/mL | 小於0.5 | 小於0.5 | 小於0.5 | 小於0.5 | - | 小於0.5 |
項 | 標準 | 比較實例4 | 比較實例5 | 比較實例6 | |||
初始 | 1 個月 | 初始 | 1 個月 | 初始 | 1 個月 | ||
pH | 6.0~9.0 | 8.3 | 8.2 | 8.3 | 8.2 | 8.1 | 8.1 |
游離脂肪酸 | ≤8.0 mg/mL | 2.6 | 3.1 | 2.3 | 2.8 | 2.2 | 2.8 |
平均顆粒 | ≤500 nm | 200 | 197 | 200 | 210 | 190 | 195 |
最大顆粒 | ≤1 μm | 0.39 | 0.30 | 0.35 | 0.32 | 0.33 | 0.41 |
分散度 | ≤0.25 | 0.09 | 0.04 | 0.06 | 0.04 | 0.06 | 0.12 |
溶血磷脂醯膽鹼 | ≤2 mg/mL | 小於0.5 | 小於0.5 | 小於0.5 | 小於0.5 | 小於0.5 | 小於0.5 |
實驗實例 6 :對脂質營養素輸注之穩定性測試 2
在長期(25℃/RH 60%)、加速(40℃/RH 75%)儲存條件下,對上述實例1及比較實例4至6進行六個月穩定性評估,使得其結果示於下表5中。
【表5】
項 | 標準 | 實例1 | 比較實例4 | ||||
初始 | 長期6M | 加速6M | 初始 | 長期6M | 加速6M | ||
pH | 6.0~9.0 | 8.3 | 8.2 | 7.2 | 8.3 | 8.1 | 7.1 |
游離脂肪酸 | ≤8.0 mg/mL | 2.4 | 3.3 | 6.0 | 2.6 | 3.3 | 6.6 |
平均顆粒 | ≤500 nm | 192 | 223 | 219 | 200 | 220 | 232 |
最大顆粒 | ≤1 μm | 0.30 | 0.29 | 0.47 | 0.39 | 0.35 | 0.39 |
分散度 | ≤0.25 | 0.04 | 0.01 | 0.13 | 0.09 | 0.04 | 0.06 |
溶血磷脂醯膽鹼 | ≤2 mg/mL | 小於 0.5 | 0.54 | 1.18 | 小於 0.5 | 0.49 | 1.35 |
項 | 標準 | 比較實例5 | 比較實例6 | ||||
初始 | 長期6M | 加速6M | 初始 | 長期6M | 加速6M | ||
pH | 6.0~9.0 | 8.3 | 8.0 | 7.1 | 8.1 | 8.1 | 7.0 |
游離脂肪酸 | ≤8.0 mg/mL | 2.3 | 3.3 | 5.8 | 2.2 | 3.3 | 5.8 |
平均顆粒 | ≤500 nm | 201 | 236 | 224 | 190 | 213 | 221 |
最大顆粒 | ≤1 μm | 0.35 | 0.39 | 0.43 | 0.33 | 0.55 | 0.35 |
分散度 | ≤0.25 | 0.06 | 0.05 | 0.09 | 0.06 | 0.20 | 0.04 |
溶血磷脂醯膽鹼 | ≤2 mg/mL | 小於 0.5 | 0.64 | 1.18 | 小於 0.5 | 0.56 | 1.14 |
從上表5中可見,已確定,儘管包含大量多不飽和脂肪酸,但與比較實例5及6相比,實例1就品質而言係穩定的。然而,從包含相對最多量Ω-3脂肪酸之比較實例4之結果判斷,在考慮實際產物有效期(從製造日期起24個月)之情況下,可假定Ω-3脂肪酸之濃度存在限制(表5)。
實驗實例 7 :對輸液製劑之品質評估
對以上實例2及3中製備之輸液之各隔室流體及與第一至第三隔室流體混合之流體進行品質評估,使得其結果示於下表6中。
【表6】
分類 | 項 | 標準 | 實例2 | 實例3 |
第一隔室流體 | 性質 | 透明及無色至淺黃色溶液 | 適宜 | 適宜 |
pH | 5.4 - 5.8 | 5.6 | 5.6 | |
第二隔室流體 | 性質 | 無色及透明溶液 | 適宜 | 適宜 |
pH | 3.5 - 5.5 | 4.1 | 4.5 | |
純度 | 0.25或更小之吸光度 | 0.04 | 0.01 | |
第三隔室流體 | 性質 | 象牙白均質乳液 | 適宜 | 適宜 |
pH | 6.0 - 9.0 | 8.5 | 8.2 | |
脂肪總量 | 199 – 219 mg/mL | 208 | 207 | |
游離脂肪酸 | ≤8.0 mEq/L | 2.5 | 2.5 | |
分散度 | 平均顆粒: ≤500 nm | 247 | 232 | |
最大顆粒: ≤1 μm | 0.46 | 0.39 | ||
分散度: ≤0.25 | 0.07 | 0.04 | ||
粒度 | 1.5 μm或更大: ≤2% | 0.57 | 0.39 | |
5 μm或更大:≤0.05% | 0.00 | 0.00 | ||
溶血磷脂醯膽鹼 | ≤2 mg/mL | 0.6 | 0.6 | |
混合物 | 性質 | 白色乳液 | 適宜 | 適宜 |
pH | 5.5 ~ 5.7 | 5.6 | 5.6 | |
粒度 | 最大顆粒7 μm或更大:0% | 0 | 0 | |
無菌法 | 無菌生長 | 適宜 | 適宜 | |
內毒素 | ≤0.5 EU/mL | 0.25或更小 | 0.25或更小 |
從上表6中可見,已確定,本發明之輸液製劑適用於所有針對品質所評估之項。特定言之,已確定,穩定性沒有問題,因為0.00%為顆粒5 μm或更大之比例(PFAT 5,直徑>5 μm之脂肪小球之百分比),與產物之安全性密切相關(在一些動物測試模型(豚鼠模型)中之組織學轉化,在肝及肺中出現疾病症狀(大鼠模型)等)。
圖1為顯示根據Ω脂肪酸比例之抗發炎效應之圖。
圖2為顯示根據Ω脂肪酸比例對免疫力下降之抑制效應之圖。
圖3為顯示根據Ω脂肪酸比例之血細胞指數之圖。
圖4為顯示根據Ω脂肪酸比例之血清生化指數之圖。
Claims (16)
- 一種用於預防或治療免疫受損疾病之醫藥組合物,其包含大豆油、橄欖油、中鏈三酸甘油酯及魚油之醫藥組合物,其中該醫藥組合物包含重量比為1:0.75至1:1.25之Ω-3及Ω-6脂肪酸。
- 如請求項1之醫藥組合物,其中Ω-3及Ω-6脂肪酸之重量比為1:1。
- 如請求項1之醫藥組合物,其中該等Ω-3脂肪酸為選自由α-亞麻酸(ALA)、二十碳五烯酸(EPA)及二十二碳六烯酸(DHA)組成之群之至少一者。
- 如請求項1之醫藥組合物,其中該等Ω-3脂肪酸所提供之每日量為0.1至0.2g/kg/天。
- 如請求項1之醫藥組合物,其中該等Ω-6脂肪酸為選自由亞油酸、γ-亞麻酸、金盞酸、二十碳二烯酸、二高-γ-亞麻酸、花生四烯酸、二十二碳二烯酸、二十二碳四烯酸、二十二碳五烯酸、二十四碳四烯酸及二十四碳五烯酸組成之群之至少一者。
- 如請求項1之醫藥組合物,其中該組合物抑制IL-1β之表現。
- 如請求項1之醫藥組合物,其中該等免疫受損疾病係選自由以下組成 之群:哮喘、季節性或常年性鼻炎、過敏性鼻炎、結膜炎、異位性皮膚炎、蕁麻疹、紅細胞溶血、急性腎小球腎炎、流感、慢性疲勞及癌症。
- 如請求項1之醫藥組合物,其中該組合物為非經腸投與。
- 如請求項1之醫藥組合物,其中該組合物包含選自由乳化劑、滲透調節劑、pH調節劑及抗氧化劑組成之群之至少一種添加劑。
- 一種輸液製劑,其包含含有大豆油、橄欖油、中鏈三酸甘油酯及魚油之組合物,其中該組合物包含重量比為1:0.75至1:1.25之Ω-3及Ω-6脂肪酸。
- 如請求項10之輸液製劑,其中該輸液製劑中所包含之Ω-3及Ω-6脂肪酸之重量比為1:1。
- 如請求項10之輸液製劑,其中該輸液製劑係接收在單個隔室中。
- 如請求項10之輸液製劑,其中該輸液製劑係接收在複數個隔室中,該等複數個隔室以可連接方式彼此分隔,以便在使用時可混合製劑。
- 如請求項13之輸液製劑,其中該等隔室係被分成第一隔室、第二隔室及第三隔室,其中該第一隔室接收用於提供胺基酸及電解質之第一隔室流體;該第二隔室接收用於提供糖之第二隔室流體;及該第三隔室接收用 於提供脂肪之第三隔室流體,且其中該第三隔室流體包含大豆油、橄欖油、中鏈三酸甘油酯及魚油,及包含重量比為1:0.75至1:1.25之Ω-3及Ω-6脂肪酸。
- 如請求項14之輸液製劑,其中該第一隔室接收該第一隔室流體,基於100mL該第一隔室流體計,該第一隔室流體包含2.07g L-丙胺酸、1.15g L-精胺酸、1.03g甘胺酸、0.48g L-組胺酸、0.60g L-異白胺酸、0.73g L-白胺酸、0.725g L-離胺酸鹽酸鹽、0.40g L-甲硫胺酸、0.56g L-苯丙胺酸、0.68g L-脯胺酸、0.50g L-絲胺酸、0.10g牛磺酸、0.42g L-蘇胺酸、0.18g L-色胺酸、0.04g L-酪胺酸、0.58g L-纈胺酸、74mg二水合氯化鈣、418mg無水甘油磷酸鈉、562mg水合乙酸鈉、247mg七水合硫酸鎂、448mg氯化鉀及2.3mg七水合硫酸鋅;其中該第二隔室接收該第二隔室流體,基於100mL該第二隔室流體計,該第二隔室流體包含14.3g或46.2g一水合葡萄糖;及其中該第三隔室接收該第三隔室流體,基於100ml該第三隔室流體計,該第三隔室流體包含4.0g純化大豆油、4.0g中鏈三酸甘油酯、5.5g純化橄欖油及6.5g純化魚油,及包含重量比為1:0.75至1:1.25之Ω-3及Ω-6脂肪酸。
- 一種包含大豆油、橄欖油、中鏈三酸甘油酯及魚油之組合物之用途,其中該組合物包含重量比為1:0.75至1:1.25之Ω-3及Ω-6脂肪酸,其用於製備用於預防或治療免疫受損疾病之醫藥製劑。
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