TW202126310A - 芸香苷組成物 - Google Patents
芸香苷組成物 Download PDFInfo
- Publication number
- TW202126310A TW202126310A TW109130986A TW109130986A TW202126310A TW 202126310 A TW202126310 A TW 202126310A TW 109130986 A TW109130986 A TW 109130986A TW 109130986 A TW109130986 A TW 109130986A TW 202126310 A TW202126310 A TW 202126310A
- Authority
- TW
- Taiwan
- Prior art keywords
- rutin
- composition
- water
- vitamin
- arginine
- Prior art date
Links
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- 229960004555 rutoside Drugs 0.000 title claims abstract description 91
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Images
Classifications
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Abstract
一種包含芸香苷、L-精胺酸及一抗壞血酸之鹼鹽的水溶性組成物,其中該芸香苷、L-精胺酸及該抗壞血酸之鹼鹽之間的莫耳比率為1: 1.6-3.0: 0.1-2.0。
Description
本發明係有關於芸香苷組成物。
發明背景
芸香苷係一種O-醣苷基類黃酮,其展現廣泛的生物活性。
舉例而言,其已顯示可預防血液凝塊之形成。預防血液凝塊可以幫助降低發展危及生命狀況之機會,諸如心肌梗塞、中風、肺栓塞及深層靜脈血栓。參見Punithavathi et al., Cardiovasc. Toxicol., 2010, 10(3):181-189, Ortolani et al., Transplant Proc., 1995, 27(5):2877-2888), Morling et al. 2013, Cochrane Database Syst. Rev. 4:Apr 30, and Morling et al., 2018, Cochrane Database Syst Rev. 11:Nov 8。
在另一例子中,芸香苷已被測試用於治療慢性靜脈功能不全(chronic venous insufficiency, CVI ),CVI係一種由瓣膜功能異常所導致之常見疾病,其伴隨或不伴隨通常發生在下肢之阻塞。
然而,芸香苷因為不良吸收而具有低生體可用率,限制其作為一治療劑之潛力。已開發具有較高水溶性之經酶促修飾的芸香苷(enzymatically modified rutin, EMR)以改善芸香苷的生體可用率。參見Toyo Sugar Refining Co., Ltd HP (alfa G-rutin)。然而,EMR係一種具有至少3種生物活性芸香苷衍生物之混合物。參見Akiyama et al., J. Food Hyg. Soc. Japan, 1999, 41:54-60。根據目前美國聯邦藥物管理局指南,在人體中使用此種活性組分之混合物作為一藥物係不切實際。
需要開發展現芸香苷之高口服吸收且具有經改善之水溶性但不具有上述缺點的組成物。
發明概要
為滿足上述需求,提供一種水溶性組成物,其含有芸香苷、L-精胺酸及一抗壞血酸之鹼鹽。在該組成物中,該芸香苷、L-精胺酸及該抗壞血酸之鹼鹽之間的莫耳比率為1: 1.6-3.0: 0.1-2.0。
在以下描述中闡明本發明之細節。從該詳細描述、該等圖式及該等所附請求項,本發明之其他特徵、目的及優點將顯而易見。
較佳實施例之詳細說明
如上所述,揭露一種水溶性組成物,其含有L-精胺酸、芸香苷及一抗壞血酸鹼鹽。此等3種成分之間的莫耳比率為1: 1.6-3.0: 0.1-2.0。在本發明之另一組成物中,該比率為1: 1.8-2.8: 0.2-1.5。一例示性水溶性組成物含有芸香苷、L-精胺酸及一抗壞血酸之鹼鹽,其莫耳比率為1: 2.3: 0.42。
值得注意地,該抗壞血酸之鹼鹽可以係一鈉鹽或一鉀鹽。在一特定的組成物中,該鹼鹽係一鈉鹽。
除了芸香苷、L-精胺酸及一抗壞血酸之鹼鹽以外,該水溶性醫藥組成物亦可以包括維生素B1、維生素B3、維生素B6、維生素B9或維生素B12。在該組成物中芸香苷與每種水溶性維生素之莫耳比率可以係1: 0.01-0.1。
上述該等具有芸香苷、L-精胺酸及抗壞血酸之鹼鹽的水溶性組成物可以藉由在美國專利申請案第62/661,255號及第62/720,651號,以及國際申請案第PCT/JP2019/017262號中所述之方法製備,其全部內容併入本文中。
在該水溶性組成物中,芸香苷可以係以10 wt%或更高(例如,20 wt%或更高,30 wt%或更高,及50 wt%或更高)的含量存在。L-精胺酸亦係以10 wt%或更高(例如,20 wt%或更高,30 wt%或更高,及50 wt%或更高)存在。該抗壞血酸之鹼鹽係以2 wt%或更高(例如,4 wt%或更高,6 wt%或更高,及10 wt%或更高)存在。
該水溶性組成物可以係以固體形式或水性形式被摻入用於醫藥、醫療、食品保存或化妝用途之調配物中。
舉例而言,該水溶性組成物可以被調配成一液體、一膠囊、一錠劑、一丸劑或一凝膠以用於口服投藥。該呈膠囊或錠劑形式之組成物可以具有一腸溶膜衣。
該等用於口服投藥之調配物亦可以含有一醫藥活性劑、一醫藥可接受之賦形劑或其等之組合。此等調配物可以係一藥物、一膳食補充品、一天然保健品、一化妝品、一食品或一飲料。
若被調配用於局部投藥,該組成物可以係一溶液、一擦劑、一洗劑、一乳劑、一軟膏、一糊劑、一凝膠或一乳膠(emulgel)。局部調配物亦可以含有一醫藥活性劑、一局部可接受之賦形劑或其等之組合。此等調配物可以係一化妝品、一護膚品或一藥物。
無需進一步闡述,相信本發明所屬技術領域中具有通常知識者可以基於以上描述最大程度地利用本發明。因此,以下具體實施例應被解釋為僅用於說明,而不以任何方式限制本揭露內容之其餘部分。在本文中所引用之所有公開文獻均以全文引用之方式併入本文中。
實施例1:一水性芸香苷/L-精胺酸/抗壞血酸組成物之製備
藉由將0.0071 mol芸香苷與一含有0.020 mol L-精胺酸之水性溶液混合,將該混合物加熱至80 ℃直至該芸香苷完全地溶解,並添加0.0010 mol抗壞血酸鈉,以在水中製備一含有芸香苷、L-精胺酸及抗壞血酸鹽之組成物。
在冷卻上述溶液之後,藉由將該混合物加熱至50 ℃,並在0小時、5小時及24小時之後藉由HPLC定量餘留之完整芸香苷的量,以測試芸香苷的穩定性。結果顯示在該溶液中完整芸香苷的量在50 ℃下在第5小時及第24小時分別為芸香苷之初始量的100%及97.2%。
進行一類似的研究以評估一與芸香苷相關之類黃酮,亦即兒茶素的穩定性,在使用L-精胺酸及抗壞血酸鈉將其溶解之後。餘留在該溶液中之完整兒茶素的量在50℃下在5小時及24小時之後分別為30.8%及2.3%。出乎意料的是在相同的條件下,在24小時之後僅有2.8%之芸香苷降解,相較於97.7%之兒茶素降解。
實施例2:一固體芸香苷/L-精胺酸/抗壞血酸組成物之製備
藉由將125.0 g的L-精胺酸(0.72 mol)溶解於經加熱至45 ℃的650 ml水中,添加22.9 g的L-抗壞血酸鈉鹽(0.12 mol)及29.9 g的氫化糊精,並攪拌直至完全地溶解,以製備第二種芸香苷/L-精胺酸/抗壞血酸鹽組成物。將170.3 g的芸香苷三水合物(0.26 mol)添加至該溶液中,並將所得之混合物在80 ℃下加熱30分鐘。該芸香苷完全溶解後,對該溶液進行噴霧乾燥並以80網目篩分,得到一黃橙色固體組成物(326.9 g)。
實施例3:芸香苷醫藥調配物之製備
使用在下列表1中所示之成分製備芸香苷/抗壞血酸鹽以及芸香苷/ L-精胺酸/抗壞血酸鹽之調配物。針對溶解研究,該等調配物係按原樣使用。針對臨床研究,該等調配物被囊封於由Capsugel所製造之尺寸#1耐酸延遲釋放羥丙基甲基纖維素膠囊(DRcapsTM
)中。
表1.芸香苷調配物成分
實施例4:溶解度測試
組分 | 調配物1 | 調配物2 |
芸香苷 (mg) / (w/w %) | 250 mg / 56.7% | 250mg / 42.4% |
L-精胺酸 (%) | - | 31.0% |
抗壞血酸鈉鹽 (w/w %) | 7.7% | 5.8% |
糊精 (w/w %) | 29.7% | 16.4% |
脂肪酸甘油酯 (w/w %) | 5.9% | 4.4% |
總和 (w/w %) | 100% | 100% |
如下所述,測試來自於調配物1及調配物2之芸香苷溶解於水中之能力。
將一定量之含有250 mg芸香苷的調配物1以及一定量之含有250 mg芸香苷的調配物2分別添加至單獨的25 mL蒸餾水中,並攪拌30秒。在取出一等分試樣之後(0分鐘),在緩慢攪拌下在37℃下加熱每個混合物。在熱處理開始之後的第5分鐘及第30分鐘,從每個混合物收集等分試樣。使每個等分試樣通過一0.45 μm過濾器,並藉由HPLC測量在該濾液中的芸香苷濃度。該等結果係顯示於下列表2中。
表2.芸香苷之水溶解度
培養時間 | 調配物1 | 調配物2 | 倍數差異 |
0分鐘 | 0.036 mg/ml | 8.4 mg/ml | 210 |
5分鐘 | 0.064 mg/ml | 9.6 mg/ml | 160 |
30分鐘 | 0.073 mg/ml | 9.8 mg/ml | 140 |
結果顯示,來自於調配物2之芸香苷所溶解的量,亦即芸香苷/L-精胺酸/抗壞血酸鹽,係高於來自於不含L-精胺酸之調配物I之芸香苷所溶解的量140至210倍。顯然,相較於調配物1,調配物2含有顯著較多的可溶性芸香苷。
實施例4:在Caco-2細胞中的滲透作用研究
測量一藥物至經培養之腸道Caco-2細胞中的滲透作用,以預測口服給藥時該藥物的相對吸收速率。
將上述實施例3中的該等調配物單獨地溶解於一溶液中。將每種溶液之一500 µL等分試樣添加至已培養19天之Caco-2細胞的頂面,並將2,000 µL之HBSS緩衝液置於該等細胞的底側面。將該等細胞在一培養箱中在37℃下培養2小時,之後從該等細胞的頂面及底側面回收培養基。藉由HPLC測定在培養基中的芸香苷濃度,並藉由以下方程式確定從頂面至底側面的吸收程度:
該等結果係顯示於圖1中。相較於含有芸香苷及抗壞血酸鹽但缺乏L-精胺酸之調配物1,含有芸香苷、L-精胺酸及抗壞血酸鹽之調配物2的滲透(吸收)速率顯著增加18倍。
實施例5:臨床藥物動力學研究
進行一隨機臨床藥物動力學研究,以比較在禁食條件下以單劑量對8名志願者投予上述實施例2中的2種不同芸香苷調配物。年齡介於25至39歲之間且具有身體質量指數數值在18.6-24.7之範圍內的健康男性參與本研究。
如上所述製備含有在表1中所顯示之調配物1及調配物2的膠囊。每位志願者服用(i) 4個含有調配物1之膠囊(芸香苷/抗壞血酸鹽;總計1000 mg芸香苷),(ii) 2個含有調配物2之膠囊(芸香苷/L-精胺酸/抗壞血酸鹽;總計500 mg芸香苷),或(iii)根據先前隨機之順序在3個測試日投予4個調配物2之膠囊(芸香苷/L-精胺酸/抗壞血酸鹽;1000 mg芸香苷)。
按照既定程序,測量在服藥之前(0小時)以及在服藥之後0.5小時、1小時、2小時、4小時及8小時從該等參與者取出之血液樣品中的芸香苷水平,而某些樣品在服藥之後48小時被取出。更具體地,為了測量芸香苷水平,首先處理從每個血液樣品所製備之血漿,以將芸香苷及其代謝物去共軛(deconjugate)成糖苷配基(aglycones)、槲皮素(quercetin)及異鼠李素(isorhamnetin),隨後藉由HPLC對其進行定量。
簡言之,將200 µl血漿樣品與10 µl 10%二硫蘇糖醇及50 µl 0.58 mol/L醋酸混合。在37℃下在0.1 M醋酸鈉緩衝液(pH5.0)中以100 U之β-葡萄糖醛酸酶H-5型(其具有β-葡萄糖醛酸酶及硫酸酯酶,亦即去共軛作用活性)處理該混合物120分鐘。
在去共軛作用之後,將500 µl的10 mM草酸添加至每個樣品中,並將該混合物以10,000 xg離心5分鐘。依製造商(Waters, Milford MA USA)指示,使用預調節之Oasis HLB管匣對所有經處理之樣品進行固相萃取。經萃取之析出液在氮氣下蒸發,在甲醇中復原,並藉由將每個析出液裝載至一C18管柱(Waters ACQUITY UPLC BEH; 1.7 µm, 2.1 x 100 mm)以進行HPLC分析,運用0.1%甲酸於水中/0.1%甲酸於乙腈HPLC中之梯度溶劑系統,並使用ACQUITY UPLC I-class Plus・Xevo TQ-S micro (Waters)檢測槲皮素及異鼠李素的存在。使用由真實的槲皮素及異鼠李素內標(internal standards)製成的標準曲線計算每種糖苷配基的濃度。在上述條件下,槲皮素及異鼠李素的分析極限為3.3 nM。
該等結果係顯示於圖2及圖3中。
圖2顯示在攝入如芸香苷/L-精胺酸/抗壞血酸鹽之500 mg芸香苷以及在攝入亦如芸香苷/L-精胺酸/抗壞血酸鹽之1000 mg芸香苷之後的48小時期間,共軛芸香苷代謝物之血漿濃度的時間進程(time course)。該等代謝物之血漿濃度穩定地增加,在攝入之後的第8.5小時(500 mg)及第9.3小時(1000 mg)達到最高水平。在24小時之後水平降低至背景。
由與圖2所描繪相似之曲線所計算之藥物動力學數值係顯示於下列表3中。
表3.芸香苷組成物之藥物動力學
參數 | 處理 | |
芸香苷/L-精胺酸/抗壞血酸鹽 500 mg | 芸香苷/L-精胺酸/抗壞血酸鹽1000 mg | |
AUC (μmol·h/L) (0-8 h) | 1.20±0.21 | 1.93±0.35 |
Cmax (μM) | 0.41±0.06 | 0.65±0.08 |
Tmax (h) | 8.5±0.7 | 9.3±0.8 |
AUC (μmol·h/L) (0-∞ h) | 4.60±0.50 | 8.35±1.14 |
圖3顯示在服用如芸香苷/抗壞血酸鹽之500 mg芸香苷、如芸香苷/L-精胺酸/抗壞血酸鹽之500 mg芸香苷、及亦如芸香苷/L-精胺酸/抗壞血酸鹽之1000 mg芸香苷之後的8小時期間,共軛芸香苷代謝物之血漿濃度的時間進程。芸香苷/L-精胺酸/抗壞血酸鹽500 mg及1000 mg兩者在第8小時的藥物動力學曲線顯示,血漿中芸香苷代謝物的出現速度明顯快於不含L-精胺酸之芸香苷。
由與圖3所描繪相似之曲線所計算之藥物動力學數值係顯示於下列表4中。
表4.芸香苷及芸香苷組成物之比較藥物動力學
參數 | 處理 | ||
芸香苷1000mg | 芸香苷/L-精胺酸/抗壞血酸鹽 500mg | 芸香苷/L-精胺酸/抗壞血酸鹽 1000mg | |
AUC (μmol·hr/L) (0-8 h) | 0.49±0.15 | 1.20±0.21 | 1.93±0.35 |
Cmax (μM) | 0.29±0.09 | 0.37±0.06 | 0.53±0.11 |
Tmax (hr) | 8.0±0 | 7.5±0.3 | 7.5±0.3 |
芸香苷/L-精胺酸/抗壞血酸鹽500 mg及1000 mg之經計算的曲線下面積(AUC)顯示一劑量依賴關係。進一步,芸香苷/L-精胺酸/抗壞血酸鹽500 mg及1000 mg從0-8小時的AUCs分別比不含L-精胺酸之芸香苷的AUC高約2.5倍及4.0倍。顯然,芸香苷與L-精胺酸及抗壞血酸鹽結合可顯著地改善芸香苷的口服吸收。
其他具體態樣
在此說明書中所揭露之所有特徵可以以任何組合來組合。在此說明書中所揭露之每個特徵可以由具有相同、等同或相似目的之替代特徵所代替。因此,除非另有明確說明,否則所揭露之每個特徵僅是一系列等同或相似特徵的一範例。
此外,根據以上描述,本發明所屬技術領域中具有通常知識者可以容易地確定本發明之必要特徵,並且在不脫離本發明之精神及範圍的情況下,可以對本發明進行各種改變及修改以使其適應各種用途及條件。因此,其他實施態樣亦在申請專利範圍之內。
無
以下描述參考該等隨附圖式,其中:
圖1係一顯示調配物1(芸香苷)及調配物2(芸香苷/精胺酸)至Caco-2細胞中之滲透比率(%)的條形圖;
圖2係一血漿中芸香苷濃度對時間的圖;及
圖3係一血漿中芸香苷濃度對時間的圖。
Claims (18)
- 一種包含芸香苷、L-精胺酸及一抗壞血酸之鹼鹽的水溶性組成物,其中該芸香苷、L-精胺酸及該抗壞血酸之鹼鹽之間的莫耳比率為1: 1.6-3.0: 0.1-2.0。
- 如請求項1之水溶性組成物,其中該抗壞血酸之鹼鹽係一鈉鹽或一鉀鹽。
- 如請求項2之水溶性組成物,其中該組成物係一選自於由一液體、一膠囊、一錠劑、一丸劑及一凝膠所組成之群組的口服調配物。
- 如請求項2之水溶性組成物,其中該組成物係一選自於由一溶液、一擦劑、一洗劑、一乳劑、一軟膏、一糊劑、一凝膠及一乳膠(emulgel)所組成之群組的局部調配物。
- 如請求項2之水溶性組成物,其中該組成物係一儲藏穩定食品。
- 如請求項1之水溶性組成物,其進一步包含維生素B1、維生素B3、維生素B6、維生素B9或維生素B12。
- 如請求項6之水溶性組成物,其中該組成物係一選自於由一液體、一膠囊、一錠劑、一丸劑及一凝膠所組成之群組的口服調配物。
- 如請求項6之水溶性組成物,其中該組成物係一選自於由一溶液、一擦劑、一洗劑、一乳劑、一軟膏、一糊劑、一凝膠及一乳膠所組成之群組的局部調配物。
- 如請求項2之水溶性組成物,其進一步包含維生素B1、維生素B3、維生素B6、維生素B9或維生素B12。
- 如請求項2之水溶性組成物,其中該芸香苷、L-精胺酸及該抗壞血酸之鹼鹽之間的莫耳比率為1: 1.8-2.8: 0.2-1.5。
- 如請求項10之水溶性組成物,其中該芸香苷、L-精胺酸及該抗壞血酸之鹼鹽之間的莫耳比率為1: 2.3: 0.42。
- 如請求項10之水溶性組成物,其中該抗壞血酸之鹼鹽係一鈉鹽或一鉀鹽。
- 如請求項10之水溶性組成物,其中該組成物係一選自於由一液體、一膠囊、一錠劑、一丸劑及一凝膠所組成之群組的口服調配物。
- 如請求項10之水溶性組成物,其中該組成物係一選自於由一溶液、一擦劑、一洗劑、一乳劑、一軟膏、一糊劑、一凝膠及一乳膠所組成之群組的局部調配物。
- 如請求項10之水溶性組成物,其中該組成物係一食物的保存期限改善劑。
- 如請求項10之水溶性組成物,其進一步包含維生素B1、維生素B3、維生素B6、維生素B9或維生素B12。
- 如請求項16之水溶性組成物,其中該組成物係一選自於由一液體、一膠囊、一錠劑、一丸劑及一凝膠所組成之群組的口服調配物。
- 如請求項16之水溶性組成物,其中該組成物係一選自於由一溶液、一擦劑、一洗劑、一乳劑、一軟膏、一糊劑、一凝膠及一乳膠所組成之群組的局部調配物。
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WO2019230013A1 (ja) | 2018-06-01 | 2019-12-05 | 太陽化学株式会社 | フラボノイド-シクロデキストリン包接化合物を含有する組成物 |
-
2020
- 2020-02-13 US US16/790,330 patent/US10918654B1/en active Active
- 2020-02-17 EP EP20157589.1A patent/EP3795140B1/en active Active
- 2020-02-20 JP JP2020026897A patent/JP6763590B1/ja active Active
- 2020-09-09 TW TW109130986A patent/TW202126310A/zh unknown
- 2020-09-15 MX MX2021003375A patent/MX2021003375A/es unknown
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RU2763543C1 (ru) | 2021-12-30 |
MX2021003375A (es) | 2021-05-27 |
CA3118258A1 (en) | 2021-04-01 |
JP6763590B1 (ja) | 2020-09-30 |
AU2020355939B2 (en) | 2023-11-09 |
BR112021007035A2 (pt) | 2022-04-05 |
AU2020355939A1 (en) | 2022-03-10 |
WO2021060091A1 (en) | 2021-04-01 |
EP3795140A1 (en) | 2021-03-24 |
CN112912084A (zh) | 2021-06-04 |
AU2020355939C1 (en) | 2024-07-11 |
JP2021050192A (ja) | 2021-04-01 |
US10918654B1 (en) | 2021-02-16 |
CN112912084B (zh) | 2022-04-12 |
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