TWI788228B - 山竹果殼萃取物用於製備治療褥瘡的藥物的用途 - Google Patents
山竹果殼萃取物用於製備治療褥瘡的藥物的用途 Download PDFInfo
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- TWI788228B TWI788228B TW111105829A TW111105829A TWI788228B TW I788228 B TWI788228 B TW I788228B TW 111105829 A TW111105829 A TW 111105829A TW 111105829 A TW111105829 A TW 111105829A TW I788228 B TWI788228 B TW I788228B
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- husk
- mangosteen
- extract
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Abstract
本發明提供一種組合物用於製備治療褥瘡之藥物的用途,其中該組合物包含一有效劑量之山竹果殼萃取物。
Description
本發明涉及一種組合物用於製備治療褥瘡之藥物的用途。
皮膚是人體最大的器官,皮膚疾病也是種類眾多,皮膚疾病可能為急性(持續僅數分鐘至數小時)或慢性的狀況,其可能影響個體數天、數月、數年甚至一生,皮膚疾病可能為真菌性的、細菌性的、或病毒性的病況,或可能為非-感染性的、免疫性的反應,例如帶有或不帶有過敏原之發炎反應,或可能為特發性病。因此,症狀可能為各式各樣且可能從溫和的癢感、發紅與腫脹至嚴重的長膿與開放性疼痛,例如傷害性的潰爛,皮膚疾病可能實質影響個體生活的品質。
褥瘡,也稱為壓瘡,是皮膚和下層組織的局部損傷,通常發生在骨頭突出處,例如腳後跟、臀部和尾骨,通常是由於長期受壓引起的。
褥瘡的危險因子通常被認為與糖尿病、身體缺陷、認知障礙、神經衰弱或年齡較大有關。褥瘡還會引起一些併發症,例如蜂窩性組織炎、骨骼和關節感染、癌症和敗血症。
在臨床方面,2019年國際循證臨床實踐指南對治療褥瘡的策略提出了建議,包括使用臥床休息、壓力重新分配支撐面、營養支持、重
新定位、傷口護理和生物物理製劑。然而,該指南缺乏用於治療褥瘡的適當治療劑的教導。
山竹果已被研究應用於乳癌的預防及肌肉相關疾病等領域,亦被開發作為日常生活的營養補充劑及化妝品等,同時也被應用於治療急性肝炎、肝纖維化及預防肝硬化的用途。
Matsumoto等人亦研究由山竹果殼中純化出α-倒捻子素(mangostin)、β-倒捻子素、γ-倒捻子素、及甲基-β-倒捻子素,並研究該化合物對細胞周期各階段的抑制作用,顯示該化合物具有抗細胞增殖效果及抗腫瘤效應(Bioorg.Med.Chem.2005,13,6064-6069)。
本發明提供一種組合物用於製備治療皮膚疾病之醫藥組合物的用途。
具體而言,本發明提供一種組合物用於製備治療褥瘡之藥物的用途,其中該組合物包含一有效劑量之山竹果殼萃取物。該藥物亦可用於局部治療或精準治療之用途。
本發明還提供一種治療一個體中褥瘡的方法,包括給予包含一有效劑量之山竹果殼萃取物的醫藥組合物。
山竹果殼包含較軟的內果殼和較硬的外果殼。
於一較佳實施方式中,該山竹果殼係利用溶劑進行萃取,該萃取溶劑係選自由甲醇、乙醇、正-丙醇、2-丙醇、正-丁醇、丙酮、乙酸乙酯及水所組成之群組。
於另一較佳實施方式中,該山竹果殼萃取物包括山竹果殼水
萃取物及/或山竹果殼酒精萃取物。
於一較佳實施方式中,該山竹果殼萃取物為山竹果殼水萃取物。
於另一較佳實施方式中,該山竹果殼萃取物為山竹果殼酒精萃取物。
於一較佳實施方式中,該山竹果殼包括山竹果殼的外果殼/內果殼及/或山竹果殼的全果殼。
於另一較佳實施方式中,該山竹果殼是山竹果殼的外果殼。
於一較佳實施方式中,本發明之組合物可為口服或非經腸胃道製劑,該非經腸胃道製劑可為外用製劑,該外用製劑可為乳霜、乳膏、軟膏、凝膠、洗劑或貼布。
於一較佳實施方式中,本發明之山竹果殼萃取物包含α-倒捻子素(α-mangostin)及γ-倒捻子素(γ-mangostin)。
於另一較佳實施方式中,本發明之山竹果殼水萃取物包含α-倒捻子素(α-mangostin)及γ-倒捻子素(γ-mangostin)。
於又一較佳實施方式中,本發明之山竹果殼酒精萃取物包含α-倒捻子素(α-mangostin)及γ-倒捻子素(γ-mangostin)。
本發明中所稱「有效劑量」係投予至個體時達到有效結果的劑量,或者是,於體內或體外擁有所需活性的劑量。於發炎病症與自體免疫病症的情況中,與未治療比較,有效的臨床結果包括與疾病或病症有關之症候的程度或嚴重性減緩、及/或延長個體壽命、及/或提高個體生活品質。投予至個體的精確化合物量將視疾病或症狀的類型與嚴重性以及個體
特性來決定,個體特性例如個體的一般健康狀況、年齡、性別、體重與對藥物的耐受性。亦視發炎病症、自體免疫病症、過敏病症的程度、嚴重性與類型或所求免疫抑制效果來決定。熟悉本領域之技藝者依據該些及其他因素將能夠決定適當的劑量。
於一實施方式中,本發明之山竹果殼萃取物的有效劑量為0.5%(w/w)至10%(w/w);於一較佳實施方式中,本發明之山竹果殼萃取物的有效劑量為1%(w/w)至8%(w/w);於最佳實施方式中,該山竹果殼萃取物的有效劑量為1.25%(w/w)至5%(w/w)。
本發明之醫藥組合物可調配成各種口服或非經腸胃道製劑之型式。口服製劑可調配成固體製劑,例如粉末、顆粒、錠劑、膠囊等,或調配成液體製劑,例如懸浮液、乳液、糖漿等。非經腸胃道製劑可被調配成外用製劑,例如乳霜、軟膏、凝膠、洗劑、貼布等,或吸劑、氣溶膠、栓劑等。
本發明之醫藥組合物可包含醫藥上可接受賦形劑,尤其是可進一步包含預定之溶劑或油類,如果需要,並可進一步包含分散劑。
本發明所用溶劑的實例包括但不限於水、乙醇、異丙醇、1,3-丁二醇、丙二醇、甘油等。
可用於本發明之油類的實例係選自由玉米油、芝麻油、亞麻油、棉花籽油、大豆油、花生油、單-甘油酯、二-甘油酯、三-甘油酯、礦物油、深海魚鮫油角鯊烯(Squalene)、荷荷巴油(jojoba oil)、橄欖油、月見草油、琉璃苣油(Borage Oil)、葡萄籽油、椰子油、葵花籽油、乳油木果脂及其任意組合所組成之群組,但不以此為限。
溶劑及油類可單獨使用或使用其任何之組合。
有益之分散劑實例可包含卵磷脂、有機單甘油酯、山黎醇脂肪酸酯、聚氧乙烯脂肪酸酯、硬脂酸山梨醇酐酯等,但不以此為限。這些原料亦可單獨使用或使用其任何之組合。
若需要,組合物可進一步包含額外原料,例如抗微生物劑或防腐劑。
同時,習知活性成分可與組合物同時使用,只要其在本發明組合物之醫藥活性上不具有反效果即可。例如,如神經醯胺(ceramide)之潤膚霜通常作為習知異位性皮膚炎藥劑,或液體成分、例如氫羥腎上腺皮質素之類固醇、維生素A衍生物,例如棕櫚酸維生素A及/或生育酚等可與組合物一同使用。
當該醫藥組合物作為外用製劑時,可使用適當的皮膚外用製劑作為基礎原料,水性溶液、非水性溶劑、懸浮液、乳液或凍乾製劑等均可被使用,並依習知方法消毒。
在實際上被投與或施用之本發明組合物中,劑量可根據各種因素決定,例如投與路徑、年齡、性別、及病患體重、與疾病嚴重性及作為活性成分之藥劑型式。
在本發明組合物可為食品或化妝品組合物之情況,可經由適當添加至少一種食品滋養或美容可接受性載劑而製備該組合物。
食品組合物可用於或添加於例如健康食品。如本文中所使用,「健康食品」一詞表示一種與一般食品相較下具有增進功能之含本發明組合物之食品。健康食品可經由添加該組合物至一般食品而製備,或藉由
膠囊化、粉末化或懸浮液化製備。
化妝品組合物可以其本身或與其他化妝品成分一同添加,或可根據其他習知方法適當使用。化妝品包括鬚後水(aftershaves)、化妝水、乳霜、面膜及彩妝,但不以此為限。
化妝品組合物可調配成各種組合物形式,例如凝膠、乳霜、軟膏等。凝膠、乳霜及軟膏形式之組合物可根據組合物之形式使用已知方法,經由添加習知軟化劑、乳化劑及增稠劑或其他技術中已知之原料而適當地製備。
凝膠形式之組合物例如可經由添加例如三甲基醇丙烷、聚乙二醇及甘油之軟化劑、例如丙二醇、乙醇及異鯨蠟醇之溶劑、及純水製備。
乳霜形式之組合物之製備例如可經由添加脂肪醇,例如硬脂醇、荳蔻醇、山崳醇(behenyl alcohol)、花生醇、異十八醇及異鯨蠟醇;乳化劑,例如脂類,例如卵磷脂、磷脂醯膽鹼、磷脂醯乙醇胺、磷脂絲胺酸、磷酸脂肌醇及其衍生物、硬脂酸甘油酯、棕櫚酸山梨醇酯、硬脂酸山梨醇酯等;天然脂肪及油類,例如酪梨油、杏仁油、巴巴樹油(babassu oil)、琉璃苣油、山茶花油等;脂質組合物,例如神經醯胺、膽固醇、脂肪酸、植物鞘胺醇、卵磷脂等;溶劑,例如丙二醇等;及純水。
軟膏形式之組合物之製備可例如經由添加軟化劑、乳化劑及蠟,例如微晶蠟、石蠟、地蠟(ceresin)、蜜蠟、鯨蠟、凡士林等。
另一方面,本發明提供一種使用該組合物製備用於治療或緩解異位性皮膚炎之藥劑的方法。如本文中所使用,「治療或緩解」一詞意指當病患使用藥劑時,指停止或延遲疾病之病程或症狀。
圖1所示為本發明的動物實驗流程圖。圖1A為實驗時間軸;圖1B為陶瓷磁鐵(ceramic magnetic plates)的施用示意圖。
圖2為第3階段褥瘡在治療7天後的面積。控制組:未給藥;安慰劑組:賦形劑;Xantho樣品組:有效劑量為0.625%(w/w)、1.25%(w/w)、2.5%(w/w)和5%(w/w)的全果殼萃取物。結果以平均值±標準誤差(SEM)顯示之,*表示P<0.05,**表示P<0.01;統計方式:學生T檢驗。
圖3顯示第3階段褥瘡在治療7天後的圖像。控制組:未給藥;安慰劑組:賦形劑;Xantho樣品組:有效劑量為0.625%(w/w)、1.25%(w/w)、2.5%(w/w)和5%(w/w)的全果殼萃取物。
圖4所示為小鼠皮膚的組織學評估,其結果顯示,與安慰劑組相比,Xantho樣品組中,2.5%(w/w)全果殼萃取物有顯著的變化。結果以平均值±標準誤差(SEM)顯示之,*表示P<0.05,**表示P<0.01,***表示P<0.001;統計方式:學生T檢驗;圖4A為發炎的評分;圖4B為再上皮化的評分;圖4C為肉芽組織生成程度的評分;圖4D為血管新生的評分。控制組:未給藥;安慰劑組:賦形劑;2.5%:2.5%(w/w)的全果殼萃取物。
圖5為第3階段褥瘡在治療7天後的面積。控制組:未給藥;安慰劑組:賦形劑;內:山竹果殼的內果殼;外:山竹果殼的外果殼;全:山竹果殼的全果殼。結果以平均值±標準誤差(SEM)顯示之,*表示P<0.05;統計方式:學生T檢驗。
圖6顯示第3階段褥瘡在治療7天後的圖像。控制組:未給藥;安慰劑組:賦形劑;內:山竹果殼的內果殼;外:山竹果殼的外果殼;全:
山竹果殼的全果殼。
以下實施方式是非限制性的,僅代表本發明的各個方面和特徵。
實驗例
醫藥組合物的製備
取山竹果殼,將果殼乾燥至50%~95%,以溶劑(如水或10%~95%之酒精)進行萃取,濃縮取得山竹果殼萃取物。
將山竹果殼之外果殼及內果殼分離,分別將山竹果殼外果殼及山竹果殼內果殼乾燥至50%~95%,以溶劑(如水或10%~95%之酒精)進行萃取,濃縮取得山竹果殼外果殼萃取物及山竹果殼內果殼萃取物。
分別將山竹果殼之酒精及水萃取物、山竹果殼內、外果殼之酒精及水萃取物製成不同濃度的乳膏或軟膏。
動物實驗
本發明之動物實驗選用7週齡的BALB/c小鼠(購自LESCO Biotech),體重為24~30g,經獸醫檢疫1週後進入飼養室。飼養室溫度設定為21±2℃,濕度設定為30%~70%,環境設定為12/12小時明暗循環,不限量供應食物和水。
本發明的動物實驗流程圖如圖1A所示。小鼠褥瘡模型是根據Stadler等人描述的方法稍作修改後所開發的。首先使用異氟醚和O2鎮靜小鼠約50-60秒,並將小鼠背毛剃光,使用模板來標記位置,以確保在每隻小鼠上所放置的磁鐵的位置一致。接著,小鼠背部皮膚被夾在兩個直徑為12
毫米、厚度為5毫米、磁力為1000G的圓形陶瓷磁鐵(ceramic magnetic plates)之間(見圖1B)。
於每隻小鼠中以三個缺血-再灌注(IR)循環來啟動褥瘡形成。單個缺血-再灌注循環包括6小時的磁鐵放置時間,然後是18小時的釋放或休息時間。在IR循環期間,動物沒有被固定、麻醉或以其他方式處理。
所有的小鼠均被允許隨意進食和飲水。將36隻小鼠隨機分為6組(每組6隻小鼠),分別為:未給藥(標記為控制組)、安慰劑治療的賦形劑組(標記為安慰劑)和四個以有效劑量為0.625%(w/w)、1.25%(w/w)、2.5%(w/w)、5%(w/w)的山竹果全果殼萃取物治療的Xantho樣品組(標記為全果殼萃取物)。在第3階段褥瘡形成後,每天給予各種劑量的山竹果全果殼萃取物處理傷口(40.25mg/cm2),並持續7天,並在第0、4和7天觀察幾個參數,包括:潰瘍癒合、體重、食物和水的攝入量。各組的傷口面積均進行拍照,並以ImageJ軟體(ImageJ Fiji,USA)進行分析,並計算平均潰瘍分期和標準偏差。潰瘍的分級以在臨床實踐中廣泛使用的標準化分級量表進行分級,如表1所示,皮膚顏色和皮膚完整性的變化按0-4的等級分級,其中0分代表完整的正常皮膚,4分代表皮膚和皮下組織全層缺失和/或疤痕形成的病變。
組織病理學
每隻小鼠的皮膚組織都以10%磷酸鹽緩衝的福爾馬林(phosphate-buffered formalin)中固定,然後包埋在石蠟塊中。將5毫米厚的石蠟包埋組織切片安裝在載玻片上,用蒸餾水再水化,並用蘇木精(hematoxylin)和伊紅(eosin)染色。作為組織學評估的一部分,所有載玻片均使用蒙面載玻片(masked slides),並由不了解先前治療的病理學家在顯微鏡下,以50倍放大倍數(LEICA DM2700 M,美國)進行評估。測量的參數是發炎程度、上皮再生程度、肉芽組織生成程度和血管新生程度。組織學評分系統如表2所示。
統計分析
統計結果以平均值±標準誤差(SEM)顯示之,*表示P<0.05,**表示P<0.01;。統計分析係使用GraphPad Prism(8.0版)透過Dunnett事後檢驗(Dunnett’s post-hoc test)進行單向方差分析。統計顯著性的P值表示為*表示P<0.05,**表示P<0.01和***表示P<0.001。
結果
與控制組相比,治療7天後,給予有效劑量為1.25%(w/w)、2.5%(w/w)和5%(w/w)的全果殼萃取物使得第3階段褥瘡潰瘍的體積顯著減小(見圖2和圖3)。特別是,給予有效劑量為2.5%(w/w)的全果殼萃取物的組別顯示出更好的效果。*表示P<0.05,**表示P<0.01。
比較安慰劑組與用2.5%的全果殼萃取物治療褥瘡的組織學評分的評估,結果如圖4所示。在發炎評分中,圖4A顯示,除2.5%的全果殼萃取物的發炎評分下降到2.67,其餘小組的評分均在3.83~4之間。再上皮化評分如圖4B所示,除2.5%的全果殼萃取物的評分增至2外,其餘組別評分均在1~1.17之間。肉芽組織生成程度的評分如圖4C所示,除2.5%的全果殼萃取物的評分增至2外,其餘組別評分均在1~1.33之間。血管生成評分顯示於圖4D,除2.5%的全果殼萃取物的評分增加到2.67外,其餘組的評分在1~1.67之間。上述結果顯示,2.5%的全果殼萃取物對傷口和褥瘡的癒合非常有效。
進一步確認2.5%(w/w)山竹果殼萃取物的作用,將30隻7週齡BALB/c小鼠分為5組,分別為進行未給藥(標記為控制組)、給予賦形劑(標記為安慰劑組)和給予三種山竹果殼萃取物(標記為Xantho樣品組;內:內果殼萃取物;外:外果殼萃取物;全:全果殼萃取物),每組6隻小鼠。在第3階段褥瘡形成後,每天以各樣品處理傷口(40.25mg/cm2),持續7天。在第0天、第4天和第7天觀察潰瘍癒合、體重、食物和水的攝入量等幾個參數,並拍攝每組傷口面積,然後使用ImageJ軟體(ImageJ Fiji,USA)進行分析。如圖5和圖6所示,2.5%(w/w)的外果殼萃取物和全果殼萃取物顯著縮小了第3階段褥瘡潰瘍的大小,似乎外果殼萃取物對褥瘡的治療潛力最大。
儘管本發明已經被足夠詳細的描述和示例,以供所屬技術領域中具通常知識者可以製作和實施,但在不脫離本發明的精神和範圍的情況下,各種替代、修改和改進應該是顯而易見的。
所屬技術領域中具通常知識者容易理解,本發明很好地適用
於實現所述目的並獲得所提及的目的和優點以及其中固有的那些目的和優點。細胞、動物以及產生它們的過程和方法僅代表最佳實施方式,是例示性的,並不意在限制本發明的範圍。所屬技術領域中具通常知識者能想到其中的修改和其他用途,這些修改包含在本發明的精神內並且由申請專利範圍的範圍所限定。
Claims (9)
- 一種組合物用於製備治療褥瘡之藥物的用途,其中該組合物包括一有效劑量的山竹果殼萃取物,其中,該有效劑量為1.25% w/w至5% w/w。
- 如請求項1所述之用途,其中,該山竹果殼萃取物包括山竹果殼水萃取物及/或山竹果殼醇萃取物。
- 如請求項1所述之用途,其中,該山竹果殼包括山竹果殼的外果殼及/或山竹果殼的內果殼。
- 如請求項1所述之用途,其中,該山竹果殼係山竹果殼的外果殼。
- 如請求項1所述之用途,其中,該山竹果殼萃取物包括α-倒捻子素和γ-倒捻子素。
- 如請求項1所述之用途,其中,該組合物是腸胃外製劑。
- 如請求項6所述之用途,其中,該腸胃外製劑是外用製劑。
- 如請求項1所述之用途,其中,該有效劑量為0.5% w/w至10% w/w。
- 如請求項1所述之用途,其中,該有效劑量為1% w/w至8% w/w。
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