TW202038940A - 異槲皮素組成物 - Google Patents
異槲皮素組成物 Download PDFInfo
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- TW202038940A TW202038940A TW108147838A TW108147838A TW202038940A TW 202038940 A TW202038940 A TW 202038940A TW 108147838 A TW108147838 A TW 108147838A TW 108147838 A TW108147838 A TW 108147838A TW 202038940 A TW202038940 A TW 202038940A
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- Prior art keywords
- water
- vitamin
- isoquercetin
- pharmaceutical composition
- composition
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- OVSQVDMCBVZWGM-QSOFNFLRSA-N quercetin 3-O-beta-D-glucopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O OVSQVDMCBVZWGM-QSOFNFLRSA-N 0.000 title claims abstract description 68
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- GXMWXESSGGEWEM-UHFFFAOYSA-N isoquercitrin Natural products OCC(O)C1OC(OC2C(Oc3cc(O)cc(O)c3C2=O)c4ccc(O)c(O)c4)C(O)C1O GXMWXESSGGEWEM-UHFFFAOYSA-N 0.000 title abstract 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 39
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Abstract
一種水溶性藥學組成物,其包含異槲皮素、L-精胺酸,以及抗壞血酸或其之一鹼金屬鹽,其中異槲皮素、L-精胺酸以及抗壞血酸或鹼金屬鹽之間的莫耳比為1:1.6-2.6:0.16-1.95。
Description
相關申請案的交互參照
此申請案主張2019年1月24日所提申之美國臨時申請案第62/796,126號之優先權。此先前的申請案之內容以其整體併入本文中以作為參考資料。
本揭示係有關於異槲皮素組成物。
發明背景
異槲皮素是槲皮素的3-O-糖苷,而許多意想不到的生物活性已被歸因於此。例如,已有報導,異槲皮素可抑制蛋白質雙硫鍵異構酶(PDI),其為一種強烈涉及血栓形成的酵素。參見Flaumenhaft et al., Arteriosclerosis, Thrombosis, and Vasc. Biol., 2015, 35:16-23。相信的是,PDI的抑制劑(例如,異槲皮素)可預防或阻止血栓形成。
為了測試異槲皮素抑制癌症-相關的血栓形成之能力,一第II/III期臨床試驗正在進行中。參見於全球資訊網clinicaltrials.gov上的CAT IQ試驗。值得注意的是,在該試驗中所投予的異槲皮素之每日劑量為500mg與1000mg。這些劑量相較於常用的藥學劑量異常地高。可能的是,由於相對低的口服吸收,需要高劑量的異槲皮素來達至足夠的生物可利用性。
經酵素改質之具有較高水溶度的異槲皮素(EMIQ)已被開發來改善異槲皮素的生物可利用性。參見Murota et al., Arch. Bi℃hem. Biophys., 2010, 501:91-97。然而,EMIQ是至少五種具生物活性的異槲皮素衍生物之混合物。參見Akiyama et al., J. Food Hyg. Soc. Japan, 1999, 41:54-60。依據目前US Federal Drug Administration規範,不能將此種活性成分的混合物用作為人類藥物使用。
有需要去發展一藉由改善水溶解度而具有較高口服吸收且沒有上述缺點的異槲皮素。
發明概要
為了滿足上述需要,提供一種水溶性藥學組成物,其包含異槲皮素、L-精胺酸,以及抗壞血酸的鹼金屬鹽。在此組成物中,異槲皮素、L-精胺酸以及抗壞血酸的鹼金屬鹽之間的莫耳比為1:1.6-2.6:0.16-1.95。
本發明的詳細內容已描述於下面的說明中。由詳細說明、圖式並且亦由所檢附的申請專利範圍,本發明的其他特徵、目的以及優點將變得明顯。
較佳實施例之詳細說明
如上所述,本文揭示一種水溶性組成物,其包含L-精胺酸、異槲皮素,以及抗壞血酸鹼金屬鹽。這三種組分之間的莫耳比為1:1.6-2.6:0.16-1.95,較佳地,1:1.8-2.5:0.36-1.25。一種示範性水溶性組成物包含莫耳比為1:2.3:0.42的異槲皮素、L-精胺酸以及抗壞血酸的鹼金屬鹽。
特別地,該抗壞血酸的鹼金屬鹽可為鈉鹽或鉀鹽。在一個特定的組成物中,該鹼金屬鹽為鈉鹽。
除了異槲皮素、L-精胺酸以及抗壞血酸的鹼金屬鹽,該水溶性藥學組成物亦可包含維生素B1、維生素B3、維生素B6、維生素B9,或者維生素B12。異槲皮素對於在該組成物中的各個水溶性維生素之莫耳比可為1;0.01-0.1。
該水溶性藥學組成物可配製來供口服投藥或局部投藥。例如,供口服投藥的組成物可為一液體、一膠囊、一錠劑、一丸劑,以及一凝膠。若配製來供局部投藥,該組成物可為一溶液、一擦劑、一乳液、一乳霜、一軟膏、一糊劑、一凝膠,以及一乳膠。
可藉由在美國專利申請案第62/661,255號與第62/720,651號中所描述的方法來生產上述異槲皮素、L-精胺酸以及抗壞血酸的鹼金屬鹽之水溶性組成物,這些專利案的內容以其整體併入本文中。
在水溶性組成物中,異槲皮素通常以10wt%以上(例如,20wt%以上、30wt%以上,以及50wt%以上)的含量而存在。L-精胺酸亦存在有10wt%以上(例如,20wt%以上、30wt%以上,以及50wt%以上)。抗壞血酸的鹼金屬鹽存在有2wt%以上(例如,4wt%以上、6wt%以上,以及10wt%或更高)。
異槲皮素可呈水合物形式或無水形式。相似地,L-精胺酸亦可呈水合物形式或無水形式。
水溶性組成物(無論固態形式或水性形式)可呈供藥學、醫學或化妝品用途之各種不同的配方。
在一個具體例中,該組成物是呈口服配方,例如,一液體、一膠囊、一錠劑、一丸劑,以及一凝膠。一示範性組成物是呈分別由腸溶包衣所形成之膠囊或錠劑。該組成物可進一步含有一藥學活性劑、一藥學上可接受的賦形劑,或者它們的組合。此具體例包括一屬於藥品、膳食補充品、天然健康產品、化妝產品、食品產品或飲料的組成物。
在另一個具體例中,該組成物是呈局部配方,例如,溶液、擦劑、乳液、乳霜、軟膏、糊劑、凝膠以及乳膠中的一者。該組成物可進一步含有一藥學活性劑、一局部可接受的賦形劑,或者它們的組合。此具體例包括一屬於化妝產品、護膚產品或藥品的組成物。
在沒有進一步闡明的情況下,相信的是,熟習此技藝者可基於上述說明將本發明利用至最充分的程度。因此,下面的具體實例應被理解僅為例示性,而不以任何方式限制本揭示的其餘部分。此處所引用的出版物以其整體併入本發明作為參考資料。
實施例1:製備異槲皮素/L-精胺酸樣品
藉由以下來製備一示範性異槲皮素/L-精胺酸混合物:將0.01mol的異槲皮素與一含有0.02mol的L-精胺酸之水溶液進行混合,將該混合物進加熱至80℃直到異槲皮素完全溶解,然後添加0.001mol的抗血酸鈉。冷卻後,藉由以下來測試異槲皮素的安定性:將該混合物加熱至50℃並且藉由HPLC來定量在0h、5h以及24h後剩餘之完整異槲皮素的含量。結果顯示,在50℃下5h與24h後之時完整異槲皮素的含量分別為異槲皮素在該溶液中的初始含量之100%與98.1%。進行類似的研究來分析與異槲皮素有關的類黃酮(亦即兒茶素)在以L-精胺酸以及抗壞血酸鈉予以溶解後的安定性。在50℃下5h與24h後在溶液中剩餘之完整兒茶素的含量分別為30.8%與2.3%。意想不到的是,24h後只有1.9%的異槲皮素降解,相對地在相同條件下有97.7%的兒茶素降解。
藉由以下來製備第二個示範性異槲皮素/L-精胺酸混合物:首先將105.5g的L-精胺酸(0.61mol)溶解於845ml之加熱至45℃的H2
O中,接著添加20.9g的L-抗壞血酸鈉鹽(0.11mol)與46.5g的氫化聚糊精並且攪拌至完全溶解。
對上面的溶液添加127g的異槲皮素一水合物(0.26mol),並且將所形成的混合物於80℃下進熱歷時30分鐘。當異槲皮素完全溶解,將該溶液進行噴霧乾燥並且以80篩目來過篩。於真空下將殘餘的H2
O蒸發而殘留黏性油,繼而於60℃下進行真空乾燥歷時8小時,而提供一黃橙色固態組成物(253.9g)。
實施例2:膠囊配方製備
使用下面表1中所示的組分來製備異槲皮素與異槲皮素/L-精胺酸的配方。針對溶解研究,該等配方依其原樣來使用。針對臨床研究,將該等配方包覆於Capsugel所製造之尺寸#1抗酸緩釋羥丙基甲基纖維素膠囊(DRcapsTM
)。
表1. 配方內容物
實施例3:溶解度測試
成分 | 配方1 | 配方2 | 配方3 |
異槲皮素(mg)/(w/w%) | 250/77.9 | 125/32.2 | 62.5/19.9 |
L-精胺酸(%) | 26.7% | 16.6% | |
抗壞血酸Na鹽(w/w%) | 5.3% | 3.2% | |
糊精(w/w%) | 15.8% | 11.8% | 7.3% |
結晶纖維素(w/w%) | 19.0% | 46.7% | |
甘油脂肪酸酯(w/w%) | 6.3% | 5.0% | 6.3% |
加總(w/w%) | 100% | 100% | 100% |
異槲皮素從配方1與配方2溶解至H2
O中的能力被量測如下。
將適量之含有500mg異槲皮素的配方1與適量之含有250mg異槲皮素的配方2分別添加至個別的25mL蒸餾H2
O水中並攪拌歷時30s。在移除整分部分(0min.)後,在緩慢攪拌下於37℃下對各個混合物進行加熱。在開始熱處理後的5min.與30min.時從各個混合物中收取整分部分。將各個整分部分通過0.45µm過濾器並且藉由HPLC來量測濾液中的異槲皮素濃度。結果顯示於下面的表2中。
表2. 異槲皮素的水溶解度
培育時間 | 配方1 | 配方2 | 倍數差異 |
0min | 0.02 mg/ml | 7.9 mg/ml | 395 |
5min | 0.06 mg/ml | 9.9 mg/ml | 165 |
30min | 0.07 mg/ml | 9.8 mg/ml | 140 |
結果顯示,從配方2(亦即異槲皮素/L-精胺酸/抗壞血酸鹽)溶出之異槲皮素的含量比從配方1(其沒有L-精胺酸與抗壞血酸鹽)溶出之異槲皮素的含量高140至395倍。明顯地,相較於配方1,配方2含有顯著更可溶的異槲皮素。
實施例4:Caco-2細胞的通透研究
藥物至培養的腸道Caco-2細胞的通透被量測以預測當口服給藥時藥物的相對吸收率。
將在實施例2中的上述配方1與2分別添加至一溶液中。將各個樣品之500µL的整分部分添加至已培養歷時19天之Caco-2細胞的頂側,以及將2,000µL的HBSS緩衝液至於細胞的基底側。將細胞培育於培養箱中於37℃下歷時2小時,之後從細胞的頂側與基底側這兩者取出培養基。培養基中的異槲皮素濃度是藉由HPLC來進行測定,從頂側吸收至基底側的程度是藉由下列方程式來計算出:
結果顯示,含有異槲皮素而沒有L-精胺酸與抗壞血酸鹽的配方1具有0.008%的通透率,而含有異槲皮素、L-精胺酸以及抗壞血酸鹽的配方2在通透(吸收)率上展現出37-倍顯著提升至0.298%。
實施例5:臨床藥物動力學研究
進行隨機化臨床藥物動力學研究來比較在實施例2中之上述三種不同的異槲皮素配方,其以單一劑量投藥給10位在禁食條件下的自願受試者。在年齡為24歲與39歲之間且身體質量指數數值在19.6-24.3的範圍內的健康男性參予此研究。
如上所述來製備在表1中所示之含有配方1-3的膠囊。各個自願受試者在三個試驗日服用兩個膠囊,其含有(i)配方1(IQC;一共500mg異槲皮素)、(ii)配方2(IQC/Arg;一共250mg異槲皮素)或者(iii)配方3(IQC/Arg;一共125mg異槲皮素),依據先前的隨機化順序來進行投藥。
在投藥之前(0h)以及投藥之後的第0.5、1、2、4與8h,依據已確立的操作程序測量從受試者取出的血液樣品中的異槲皮素位準。更具體地,為了測定異槲皮素位準,首先對由各個血液樣品所製得的血漿進行處理以將異槲皮素代謝物解離為糖苷配基槲皮素以及異鼠李素,其接而藉由HPLC來定量。
簡言之,將200µl的血將樣品與10µl的10%二硫蘇糖醇以及50µl的0.58mol/L乙酸進行混合。於37℃下將混合物處理以配於0.1M乙酸鈉緩衝液(pH5.0)中之1000U的β-葡萄醣醛酸酶以及100U/mL的硫酸酯酶[這兩者皆源自於HP-2型羅馬蝸牛(Helix pomatia
)]歷時120min。
在解離之後,將500µl的10mM草酸添加至各個樣品中,接著將混合物於10,000x下離心歷時5min。使用預先準備的Oasis HLB匣並依據製造商(Waters, Milford MA USA)的指引來對所有的處理樣品進行固相萃取。在氮氣下蒸發所萃取出的洗出物,回溶於甲醇中,並且拿來進行界由以下的HPLC分析:將各個洗出物進樣至一C18管住(Waters ACQUITY UPLC BEH; 1.7 µm, 2.1 x 100 mm)中,使用0.1%甲酸(配於H2
O中)/0.1%甲酸(配於乙腈)的HPLC梯度溶劑系統,並且使用Ultimate 3000快速分離LC Q Exactive光譜儀來偵測槲皮素與異鼠李素的存在。各個糖苷配基的濃度是使用可信的槲皮素與異鼠李素內部標準所製得的標準曲線來計算出。在上面的情況下槲皮素與異鼠李素的分析限制為4℃下0.03µM。
藥物動力學圖譜顯示於圖1中。注意的是,投予IQC/Arg 125mg所得到的藥物動力學圖譜是相似於IQC/Arg 250mg所具者,但Cmax
與AUC數值大約為較高劑量所具者的一半,顯示出劑量-依賴的關聯性。
從相似於圖1所繪的圖譜而計算出的藥物動力學數值顯示於下面表3中。
表3.藥物動力學
參數 | 處理 | ||
IQC 500mg | IQC/Arg 250mg | IQC/Arg 125mg | |
AUC(μmol·hr/L)(0-8h) | 8.1±1.7 | 12.5±1.7 | 4.5±0.9 |
Cmax (μM) | 2.2±0.4 | 4.2±1.0 | 1.2±0.3 |
Tmax (hr) | 3.8±0.2 | 2.1±0.2 | 3.6±0.6 |
t1/2 (hr) | 1.7±0.2 | 37.2±16.1 | 4.3±1.3 |
AUC(μmol·hr/L)(0-∞h) | 9.6±2.4 | 76.0±31.4 | 6.4±1.6 |
結果顯示,無法預期地,IQC/Arg 250mg達至4.2μM的最大的血漿濃度(Cmax
),幾乎是IQC 500mg所顯示出的2.2μM之2-倍高。亦令人意外的是,對QC/Arg 250mg而言,外推至無限大的曲線下面積[AUC(0-∞h)](總藥物可利用性的估算值)幾乎是IQC 500mg的8-倍多,儘管實際上僅投予一半之多的異槲皮素。明顯地,數據顯示出異槲皮素當與L-精胺酸結合時在吸收上有統計顯著性的增進。
此外,先前所述之經酵素改質的異槲皮素(以2mg槲皮素糖苷配基/kg體重來投藥)的Cmax
與AUC(0-6h)分別為1.84µM與5.99µmol·hr/L。參見Murota等人。相對地,對IQC/Arg 250mg(以2.56mg槲皮素糖苷配基/kg體重來投藥)而言,Cmax
與AUC(0-6h)數值分別為3.32µM與9.27µmol·hr/L,顯示出儘管投予相同劑量的異槲皮素,IQC/Arg配方的異槲皮素相較於經酵素改質的異槲皮素具有更高的生物可利用性。
其他具體例
在本說明書中所揭示的所有特徵可以任何結合方式來進行組合。在本說明書中所揭示的各個特徵可置換為起到相同、等效或相似目的之替代特徵。因此,除非另外明確指出,所揭示的各個特徵僅為一系列等效或相似特徵中的一個實例。
再者,透過上面的說明,熟習此技藝者可輕易地確知本發明的必要特徵,並且可在沒有背離其精神與範疇下,對本發明做出各種不同的改變與修改以使其適用於各種不同的用途與情況。因此,其他具體例亦是在申請專利範圍內。
圖1為投予500mg的異槲皮素(IQC 500mg)以及以異槲皮素/L-精胺酸(IQC 250mg/Arg)的方式之250mg的異槲皮素之後血漿濃度對時間的圖式。
Claims (20)
- 一種水溶性藥學組成物,其包含異槲皮素、L-精胺酸,以及抗壞血酸或其之一鹼金屬鹽,其中異槲皮素、L-精胺酸以及該抗壞血酸的鹼金屬鹽之間的一莫耳比為1:1.6-2.6:0.16-1.95。
- 如請求項1的水溶性藥學組成物,其中該組成物包括該抗壞血酸的鹼金屬鹽,該鹼金屬鹽為一鈉鹽或一鉀鹽。
- 如請求項2的水溶性藥學組成物,其中該組成物是一選自於由下列所構成之群組中的口服配方:一液體、一膠囊、一錠劑、一丸劑,以及一凝膠。
- 如請求項2的水溶性藥學組成物,其中該組成物是一選自於由下列所構成之群組中的局部配方:一溶液、一擦劑、一乳液、一乳霜、一軟膏、一糊劑、一凝膠,以及一乳膠。
- 如請求項1的水溶性藥學組成物,其進一步包含維生素B1、維生素B3、維生素B6、維生素B9,或者維生素B12。
- 如請求項5的水溶性藥學組成物,其中該組成物是一選自於由下列所構成之群組中的口服配方:一液體、一膠囊、一錠劑、一丸劑,以及一凝膠。
- 如請求項5的水溶性藥學組成物,其中該組成物是一選自於由下列所構成之群組中的局部配方:一溶液、一擦劑、一乳液、一乳霜、一軟膏、一糊劑、一凝膠,以及一乳膠。
- 如請求項2的水溶性藥學組成物,其進一步包含維生素B1、維生素B3、維生素B6、維生素B9,或者維生素B12。
- 如請求項8的水溶性藥學組成物,其中該組成物是一選自於由下列所構成之群組中的口服配方:一液體、一膠囊、一錠劑、一丸劑,以及一凝膠。
- 如請求項8的水溶性藥學組成物,其中該組成物是一選自於由下列所構成之群組中的局部配方:一溶液、一擦劑、一乳液、一乳霜、一軟膏、一糊劑、一凝膠,以及一乳膠。
- 如請求項1的水溶性藥學組成物,其中異槲皮素、L-精胺酸以及該抗壞血酸的鹼金屬鹽之間的莫耳比為1:1.8-2.5:0.36-1.25。
- 如請求項11的水溶性藥學組成物,其中該抗壞血酸的鹼金屬鹽為一鈉鹽或一鉀鹽。
- 如請求項12的水溶性藥學組成物,其中該組成物是一選自於由下列所構成之群組中的口服配方:一液體、一膠囊、一錠劑、一丸劑,以及一凝膠。
- 如請求項12的水溶性藥學組成物,其中該組成物是一選自於由下列所構成之群組中的局部配方:一溶液、一擦劑、一乳液、一乳霜、一軟膏、一糊劑、一凝膠,以及一乳膠。
- 如請求項11的水溶性藥學組成物,其進一步包含維生素B1、維生素B3、維生素B6、維生素B9,或者維生素B12。
- 如請求項15的水溶性藥學組成物,其中該組成物是一選自於由下列所構成之群組中的口服配方:一液體、一膠囊、一錠劑、一丸劑,以及一凝膠。
- 如請求項15的水溶性藥學組成物,其中該組成物是一選自於由下列所構成之群組中的局部配方:一溶液、一擦劑、一乳液、一乳霜、一軟膏、一糊劑、一凝膠,以及一乳膠。
- 如請求項12的水溶性藥學組成物,其進一步包含維生素B1、維生素B3、維生素B6、維生素B9,或者維生素B12。
- 如請求項18的水溶性藥學組成物,其中該組成物是一選自於由下列所構成之群組中的口服配方:一液體、一膠囊、一錠劑、一丸劑,以及一凝膠。
- 如請求項18的水溶性藥學組成物,其中該組成物是一選自於由下列所構成之群組中的局部配方:一溶液、一擦劑、一乳液、一乳霜、一軟膏、一糊劑、一凝膠,以及一乳膠。
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US4285964A (en) | 1979-08-30 | 1981-08-25 | Continental Pharma | Salts of (+)-catechine, their preparation and use, and compositions containing these salts |
US7041652B1 (en) * | 1998-08-27 | 2006-05-09 | Merck Patent Gmbh | Ascorbate-isoquercetin compositions |
WO2000054754A2 (en) * | 1999-03-16 | 2000-09-21 | Merck Patent Gmbh | Composition comprising isoquercetin and ascorbic acid in a sustained release form |
US7691425B2 (en) * | 2003-09-29 | 2010-04-06 | San-Ei Gen F.F.I., Inc. | Method for manufacturing α-glycosylisoquercitrin, intermediate product and by-product thereof |
WO2007114304A1 (ja) * | 2006-03-29 | 2007-10-11 | San-Ei Gen F.F.I., Inc. | ベンゼン生成抑制剤およびベンゼン生成抑制方法 |
ATE504296T1 (de) | 2007-03-06 | 2011-04-15 | Rachid Ennamany | Zusammensetzung auf basis von rutin und l-lysin |
WO2009158031A2 (en) * | 2008-06-27 | 2009-12-30 | Limerick Biopharma, Inc. | Methods and compositions for therapeutic treatment |
US20120083460A1 (en) * | 2009-03-25 | 2012-04-05 | San Ei Gen F.F.I., Inc. | Readily water-soluble isoquercitrin composition |
JP6029257B2 (ja) * | 2010-06-30 | 2016-11-24 | 森永製菓株式会社 | 筋肥大促進のための食品、補助食品、及びサプリメント |
US10391096B2 (en) * | 2011-10-13 | 2019-08-27 | Quercegen Pharmaceuticals Llc | Method for treating thrombotic disorders using quercetin-containing compositions |
BE1023772B9 (fr) | 2013-05-17 | 2017-08-02 | Valore | Composition a base d'un complexe de (+)-catechine et d'acide amine pour le traitement et la prevention du cancer |
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