TW201740926A - 水溶性之親脂材料 - Google Patents
水溶性之親脂材料 Download PDFInfo
- Publication number
- TW201740926A TW201740926A TW106104804A TW106104804A TW201740926A TW 201740926 A TW201740926 A TW 201740926A TW 106104804 A TW106104804 A TW 106104804A TW 106104804 A TW106104804 A TW 106104804A TW 201740926 A TW201740926 A TW 201740926A
- Authority
- TW
- Taiwan
- Prior art keywords
- lutein
- liposome
- composition
- wslutein
- light
- Prior art date
Links
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title description 11
- 239000008206 lipophilic material Substances 0.000 title 1
- KBPHJBAIARWVSC-RGZFRNHPSA-N lutein Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=C[C@H](O)CC1(C)C KBPHJBAIARWVSC-RGZFRNHPSA-N 0.000 claims abstract description 46
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 claims abstract description 45
- 229960005375 lutein Drugs 0.000 claims abstract description 44
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 claims abstract description 44
- 239000001656 lutein Substances 0.000 claims abstract description 43
- 235000012680 lutein Nutrition 0.000 claims abstract description 43
- ORAKUVXRZWMARG-WZLJTJAWSA-N lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C ORAKUVXRZWMARG-WZLJTJAWSA-N 0.000 claims abstract description 43
- 239000002502 liposome Substances 0.000 claims abstract description 19
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- LBSFSRMTJJPTCW-DSXUQNDKSA-N (r)-[(2s,4s,5r)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol;hydrochloride Chemical compound Cl.C([C@H]([C@H](C1)C=C)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LBSFSRMTJJPTCW-DSXUQNDKSA-N 0.000 description 3
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
本發明關於一種含於微脂體中之水溶性形式之親脂分子。在一實施例中,該親脂分子為結晶葉黃素,及該葉黃素-負載的微脂體係包含於在藥品、醫療器材、及膳食補充品工業中,除了化妝品工業之外,對於咀嚼錠、營養強化的飲料、發泡錠、未塗佈的錠劑、營養棒、及功能性食品具有潛力。
Description
本申請案主張於2016年2月15日申請之美國申請序號62/295,258之優先權,及藉此它的整體併入本文參考。
本發明通常關於一種用於製造諸如類胡蘿蔔素之可溶形式之親脂化合物之方法及,更具體言之,關於一種含有高量的微脂體-包封的類胡蘿蔔素(諸如葉黃素及玉米黃素)之乳液,其適用於藥品、醫療器材、及食品工業之用途。
當開發新藥品時雖然沒有任何調節原料的適應性(indication)之指引或準則,但無論何時應盡可能使用醫藥級物質。
葉黃素係用於製藥工業(用於醫療器材)還有作為各種食品及飲料之著色劑(Scotter MJ.2011.針對歐盟之測定允許在食品中添加的天然色料之方法:評論.Food Additives and Contaminants.28(5):527-596)。天然形式的葉黃素係為晶體。因此,它不溶於數種稀釋系統,其使得它難以應用在錠狀產品(tableted products)、醫療器材及食品相關產品。故開發可溶形式的結晶葉黃素,諸如所謂的“冷水可溶性葉黃素”(cold water soluble lutein,CWSLutein)。然而,這食品級材料存在一些限制,包括在溶液中一或二天後形成變得可見的沈降物(sediments)。沈降作用可能是由於彼原料的其它組成,其還包括澱粉、葡萄糖漿及抗壞血酸。此外,這些物質的存在阻礙葉黃素釋放主要由於像剛性多醣的結構之形成作用(Amar I,Abraham A and Garti N.Solubilization Patterns of Lutein and Lutein Esters in Food Grade Nonionic Microemulsions.2003.J.Agric.Food Chem.51:4775-4781)。CWSLutein的另一問題為對光曝照不穩定性,由是利用這原料製得的所有產品需要在琥珀色容器中供應或在黑暗條件下保存。因此,急迫需要開發一醫藥級、可溶性、可分散性且穩定的含有類胡蘿蔔素的原料。
本發明關於一種親脂分子(包括葉黃素)形式之製造方法,在其它特性之中,其易於被製造且具有相關於包括冷溶劑(例如冷水)之溶解度之改進性質。我們藉利用葉黃素與剛性改質劑調配磷脂質(phospholipids)微脂體進行研究,以改質該只使用醫藥級的組分之微脂體之吸收輪廓。我們的工作顯示(1)這新穎材料在水中具有一良好的可分散性而在數月後沒有沈降作用;(2)磷脂質、剛性改質劑及親脂環境的存在幫助葉黃素遞送至眼/鼻/皮膚結構內;(3)諸如此調配物,含有磷脂質、剛性改質劑及葉黃素,在口使用之情況下,允許葉黃素之良好可分散性及更好吸收性;(4)該剛性改質劑的存在,諸如具有熔點高於50℃之二十二酸甘油酯(glyceryl behenate),具有調整該最終結構的剛性進而是吸收輪廓的潛力。還重要是慮及在殺菌(sterilization)後該產品顯現澄清且沒有明顯沈降之完全分散。又,該新穎結構允許去除以商業上可取得的形式使用的食品級賦形劑,其有助於安全產品。
這可溶於水之新穎形式的葉黃素對於在藥品、醫療器材、膳食補充品工業之用途係為重要開發,除了它在化妝品工業用途之外,對於咀嚼錠、營養強化的飲料、發泡錠、未塗佈的錠劑、營養棒、及功能性食品具有潛力。
圖1為在室溫下1及6個月後WSLutein於THF之UV/Vis光譜。可見到葉黃素的三個特徵峰。
圖2顯示在52℃下6個月後WSLutein於THF之UV/Vis光譜。在6個月後未見到葉黃素的三個特徵峰。
圖3為在30分鐘的WSLutein培養及24小時、48小時與72小時細胞恢復後之ARPE-19細胞存活之圖表。無染料的細胞用作為控制組及0.02% SDS用作為正控制組(positive control)。來自三次重複實驗的標準誤差顯示為誤差條。
圖4為在120分鐘的WSLutein培養及24小時、48小時與72小時細胞恢復後之ARPE-19細胞存活之圖表。沒有染料的細胞用作為控制組及0.02% SDS用作為正控制組。來自三次重複實驗的標準誤差顯示為誤差條。
圖5顯示在穩定性研究開始及於室溫下1個月後之WSRetidyne(A)、WSPhacodyne(B)及WSDoubledyne(C)之UV/Vis光譜。
該術語"親脂分子"如本文所用係指溶於脂質、脂肪、油及非極性溶劑之化合物。該親脂分子可為一藥物活性劑、藥物、顯影劑、治療劑、診斷劑、化合物、或組成物。親脂分子之非限制實例為葉黃素。該親脂分子可包含介於約0.001%至10%
以重量計的微脂體組成物。另一方式陳述,該親脂分子可包含介於約b.cde%至ab%以重量計的微脂體組成物,其中a為0或者1及b、c、d與e為選自0、1、2、3、4、5、6、7、8及9,除外是當a為1時b、c、d與e全部為0且a、b、c、d及e不全部為0。
該術語“微脂體”如本文所用係指包封水性隔室之單獨或多重同心的脂質雙層(concentric lipid bilayers)。該微脂體可包括天然及/或合成的脂質與界面活性劑。該微脂體圈套在該脂質薄膜中的親脂分子。本發明之這些近乎球形的脂質囊泡(lipid vesicles)之尺寸可在介於50至450nm之範圍。另一方式陳述,本發明微脂體之尺寸在介於約ab nm至約cde nm之範圍,其中a為選自5、6、7、8及9,b為選自0、1、2、3、4、5、6、7、8及9,c為選自0、1、2、3及4,d為選自0、1、2、3、4及5,及e為選自0、1、2、3、4、5、6、7、8及9,除外是當c為4及d為5時在其情況下它為0。當然a、b、c、d及e不能全部為0。
該術語“形成脂質膜之液體”如本文所用係指經乾燥後形成膜之任何含有脂質的液體。形成脂質膜之液體的非限制實例包括溶解的磷脂質,包括卵磷脂及溶血卵磷脂。
該術語“溶劑”如本文所用係指溶劑,該親脂分子可溶於其中及其可藉蒸發去除。溶劑之非限制實例為氯仿、甲醇及四氫呋喃。
該術語“剛性改質劑”如本文所用係指組成物其改質本發明微脂體之剛性及進而是吸收輪廓。合適的剛性改質劑包括具有中至長鏈的脂肪酸基團之脂肪,諸如月桂酸、肉豆蔻酸、棕櫚酸、硬脂酸、油酸、亞麻油酸、蓖麻油酸、花生酸、二十二烷酸(behenic acid)、二十三烷酸(tricosylic acid)、木蠟酸、二十五烷酸(pentacosylic acid)、蠟酸、二十七烷酸(heptacosylic
acid)、褐煤酸、二十九烷酸(nonacosylic acid)及蜜蠟酸,其具高熔點。剛性改質劑之非限制實例為二十二酸甘油酯。
實施例1
材料及方法
材料及試劑。氫化的卵脂醯膽鹼係獲自Kemin Industries(Des Moines,Iowa)之Lipoid GmbH之FloraGLO®葉黃素及二十二酸甘油酯係獲自Gattefossé(Saint-Priest,France)。CWSLutein係購自DSM(Heerlen,NL),台盼藍(trypan blue)購自Merck(Rahway,NJ)及亮藍(Brilliant blue)購自Sigma-Aldrich(St.Louis,MO)。全部有機溶劑,氯仿、甲醇及四氫呋喃(THF)也是購自Sigma-Aldrich而Quinine-HCl係購自Acros Organics(Grand Island,NY)。用於細胞毒性(cytotoxicity)研究所需的全部試劑係獲自Lonza(Basel,CH):Dulbeco氏改質的Eagle氏培養基(DMEM),Nutrient Mixture F12培養基,熱滅活的胎牛血清(Heat-inactivated fetal bovine serum)(FBS),PBS Ca2+Mg2+緩衝液,L-麩醯胺酸,丙酮酸鈉(sodium pyruvate),HEPES,青黴素及鏈黴素。細胞增殖試劑WST-1係購自Roche Applied Science(Penzberg,DE)。
WSLutein:調配物開發。為製備4公升的微脂體,於30至35℃下藉加熱將氫化的卵脂醯膽鹼、FloraGLO®與二十二酸甘油酯(表1)溶解於500mL的氯仿與甲醇(2:1 v/v),以獲得一澄清溶液。為移除該溶劑,藉一Heidolph旋轉蒸發器於40℃至50℃真空下乾燥該溶液,及在1至2小時後獲得一乾薄膜。為確保去除所有痕量的溶劑,該薄膜於室溫下真空放置至少16小時,及進行氣相層析法以確認任何殘餘物係低於25ppm。最後,於40至45℃下在磁力攪拌下藉添加蒸餾水或磷酸鹽緩衝溶液使該膜水合至少2至3小時,以獲得一混濁分散液。該混濁分散液之後藉Ultraturrax均質機(Ika Works)被均質化,於室溫下30分鐘及2000至4000rpm,以獲得大囊泡,接著使用一大型微流化器(microfluidizer)於50至60℃及1200巴下藉擠壓微粉化為一奈米尺寸範圍。重複這程序至少5次。於1atm下藉於121℃蒸汽滅菌使該磷脂二十二酸酯珠粒(phospholipids behenate beadlets)滅菌15分鐘。透過動態光散射(Nicomp 380 DLS)進行微脂體尺寸分析,如由Hupfeld等人(Hupfeld S,Holsaeter AM,Skar M,et al.根據尺寸排除-/場流-分級法藉動態/靜態光散
射之微脂體尺寸分析.2006.J Nanosci Nanotechnol.,6(9-10):3025-3031)。
可分散性及沈降性測定。這些測定在整個時間藉目視評估進行。
UV/Vis光譜分析。葉黃素係不溶於水,因此使用THF溶解葉黃素及追蹤它的UV/Vis光譜。簡言之,將1mL的樣品轉移至一10mL容量瓶及這以蒸餾水填滿。然後,將500μL轉移至一25mL容量瓶及吸量管尖端以THF清洗到該燒瓶內。利用THF使體積至25mL及在一UV/Vis光譜儀中預先以THF為空白組追蹤300至750nm的光譜。
細胞毒性研究。WSLutein原料的細胞毒性係藉在人類視網膜色素上皮(Human Retinal Pigment Epithelial,ARPE-19)細胞的比色分析來評估。將細胞在一5% CO2與95%空氣培養箱的加濕氛圍中於37℃下培養及在以10% FBS補充的DMEM之1:1混合物(vol:vol)、L-麩醯胺酸(2mM)、丙酮酸鈉(0.5mM)、HEPES(15mM)、青黴素(100U/ml)及鏈黴素(100μg/ml)中生長。使該細胞生長至一適當密度及每48至72小時更換培養基。
根據玻璃體視網膜手術(vitreoretinal surgery)的基本體積選用染料稀釋度:將0.3mL的染料注入玻璃體腔(4mL)及程序期間使8至10mL/min的液體流動(BSS,林格氏溶液,連續灌注,等等),每個手術達到600mL(在一正常60分鐘手術)及導致1/15(染料注入)、1/30(t1分鐘)、1/60(t1.5分鐘)及1/20(t3分鐘)之稀釋度。一白內障手術流量在眼睛中以120mL/min的液體估算,產生比玻璃體視網膜手術來得更高的稀釋度。
WST-1比色評估係根據製造商的推薦進行的,以測試體外細胞毒性。
簡言之,在96-孔盤中以10-12x103細胞/cm2接種APRE-19細胞。在18至22小時生長後,數種染料稀釋度(1/15,1/30,1/60及1/120)被施用至該細胞為時30或120分鐘。在培養後,以PBS Ca2+Mg2+清洗細胞三次及
之後以新鮮的培養基+2% FBS培育過夜。細胞能夠恢復24、48或72小時,添加含有10% WST-1試劑的新鮮培養基及在培養3小時後,於450nm使用一TECAM 200讀數器(TECAN Infinite M200 PRO)測量吸收度,轉譯(translating)代謝活性細胞的數量,其與活細胞數目相關聯。作為一正控制組,使用0.02%十二基硫酸鈉(SDS)。三個獨立實驗三次重複,測試每一個濃度及時間。數據係以平均值±標準偏差(SD)記錄,其使用Excel-Microsoft Office取得。
Kemin Pharma染料:利用WSLutein開發調配物。根據表2,WSLutein用以調配具亮藍(欲模擬RetidyneTM)、具台分盼藍(欲模擬PhacodyneTM)、及具兩種藍色染料(欲模擬DoubledyneTM)之染料。顏色分別為藍色、綠色及綠藍色。
熱穩定性研究。於室溫下及於52℃下1及6個月測試WSLutein穩定性。於室溫下1個月測試WSRetidyne、WSPhacodyne及
WSDoubledyne調配物它們的穩定性。含有該調配物的所有小瓶為透明的但在沒有光曝照條件之下儲存及進行重複兩次。
光穩定性研究。單獨研究WSLutein的光穩定性。再者,WSDoubledyne及DoubledyneTM(利用CWSLutein調配的,如在表2所述)之光穩定性,在琥珀色及透明的玻璃小瓶中,研究及比較。對於這些試驗,在光穩定性腔室中,選用代表數目的樣品(3)以於光曝照或以於無-光曝照之條件。
對於一新穎藥品物質或產品之光穩定性測試係以ICH Q1B Guideline被定義。簡言之,在一有效的光穩定性腔室中該樣品必須受到一光源數小時。對這類型研究在這實驗中所用的光穩定性腔室係由Autoridade Nacional do Medicamento e Produtos de Saúde I.P.(INFARMED)證實的。根據該ICH Q1B Guideline,樣品必須利用有效的化學光輻照系統併排曝照以確保達到最小光曝照,或當使用校準輻射計/勒克斯計(lux meters)監控條件時有適當的持續時間。使用兩個Quinine-HCl之2%(w/v)溶液作為光輻照控制組及曝露於光或無-光條件,與後者被包裹於鋁箔中。以這試驗,藉Abs400nm之量測可以測定足以造成任何可能降解之發生時間(incidence time)。
將染料樣品及Quinine-HCl樣品插在該光穩定性腔室及受到相同的UV及可見光條件曝露48小時。WSLutein或Doubledyne(CWS或WS)樣品之後根據所定義參數評估可能的產品降解作用:外觀、顏色、pH及滲透壓。對於WSDoubledyne及DoubledyneTM,還在一分光光度計上分析該UV-Vis光譜。使用一pH計(Metrohm 713)及一滲透壓計(Knauer,Berlin,DE)評估pH及滲透壓。測定在測試及控制組樣品的pH及滲透壓之衰減及結果使用方程式1以百分率表示。
%衰減=100-(P樣品x 100/P控制組)
方程式1. 在給定的參數(P)中測定衰減百分率。
對於pH及滲透壓,在透明(樣品)與琥珀色(控制組)小瓶之間,透過方程式1所獲得的結果比較(表5及6)。此外,對於同類型的小瓶進行光(樣品)與無-光(控制組)曝照之間的比較(表5及6)。欲與眼應用相容,pH必須在6.0至7.4內(即,pH=6.7±0.7或pH=6.7±10.45%)及滲透壓必須在250至380mOsm/L內(即,滲透壓=315±65mOsm/L或315±20.63% mOsm/L)。
因此,且建立一嚴格規範,當在條件之間的差異低於10%時結果為有效的。在該結果段落提供進一步詳細內容。
屍體眼睛研究(Cadaveric eyes study)。一很類似於WSLutein之微脂體調配物(1%磷脂質+0.05% FloraFLO)在屍體眼睛中測試它的在染色眼內膜(intraocular membranes)的功效,其為Kemin Pharma產品的目標。如先前說明7使用四個屍體眼睛(根據該ARVO的研究指南及該Helsinki的宣布之原則)及以這微脂體溶液調製的Retidyne及Phacodyne代替CWSLutein測試。由有經驗的外科醫生進行盲法實驗,使用來自表3的等級標度測定染色強度(staining intensity)。
結果
WSLutein調配物及分析。對於在藥品、醫療器材、及其它類似藥品的產品之用途,開發一新型可溶性葉黃素是重要的。一新穎葉黃素原料經調配及製造含有磷脂質剛性珠粒(氫化的卵脂醯膽鹼)、FloraGLO®葉黃素及二十二酸甘油酯,只使用高品質等級的組成。
以實際Kemin Pharma產品為基底,選擇包封在該磷脂質中的葉黃素之量。Knowing其CWS葉黃素含有5%的FloraGLO®,Kemin Pharma染料含有介於0.05%至0.1%的葉黃素。因此,欲被包封所選用的葉黃素的量為0.15%,如此將製備具相同葉黃素含量之調配物。
在所有成分溶解於有機溶劑後,去除這些溶劑及獲得一乾薄膜。這膜之後經水合、微粉化及滅菌。
在滅菌後,該產物顯露澄清及以不顯明沈降被完全分散。之後分析這原料(表4)它的溶解度及在數日後顯示於水中沒有沈降物之良好可分散性。更且,在一周後觀察到沈降現象比現有的CWSLutein見到的較不顯著。綜上所述,當相比於CWSLutein時,這新穎材料顯示為更可溶性,具低沈降傾向,及更可分散性。此外,在滅菌後粒子尺寸分析顯示葉黃素結構
被維持及該尺寸估計介於200至800nm。對於這調配物還測定滲透壓與pH及係按照藥典的眼睛生理參數(Pharmacopoeial ocular physiological parameters)(pH=7,滲透壓=171至1711)。UV/Vis光譜經分析及顯示葉黃素之三個峰特徵(圖1)。
於室溫下1及6個月研究WSLutein的穩定性及結果示於表5。圖1還顯示在1及6個月後的平均UV/Vis光譜。一於52℃下增速的研究進行6個月(表6及圖2)。
於室溫下6個月儲存後顯示該新穎WSLutein原料為穩定的(圖1及表5)。然而,由於在UV/Vis光譜未見到葉黃素峰(圖2)還有觀察到顏色上變化(表6),在較高溫(52℃)下觀察到不穩定性。
表6. 於52℃下6個月WSLuteins之穩定性研究
在透明及琥珀色小瓶中還評估這調配物的光穩定性。結果歸納於表7及8,在光-曝照與無-光曝照的樣品之間,在pH或在滲透壓未顯示明顯衰減(<10%)。又,在透明與琥珀色小瓶之間未偵測到差異性。結果證明這新穎原料對光-曝照是穩定的且可被儲存在透明小瓶中。
表8. 對於WSLutein之滲透壓及pH之%衰減:光與無-光條件之間及琥珀色與透明小瓶之間的比較
細胞毒性研究。藉測量於450nm的吸收度使用WST-1比色評估,在ARPE-19細胞中體外評估WSLutein(染料稀釋度1/15,1/30,1/60及1/120)的細胞毒性。在圖3及4中的結果顯示以染料稀釋液30分鐘或120分鐘培養這調配物及在24、48或72小時的細胞恢復後沒有細胞毒性,因為在控制組與染料-處理的細胞之間觀察到細胞存活力(cell viability)之最小差異性。
利用WSLutein調配的染料之分析。該新穎WSLutein原料被用以調配DoubledyneTM、RetidyneTM及PhacodyneTM(見表2)。分析這些調配物它們的顏色、外觀、pH、滲透壓及UV/Vis光譜(表9)。更且,研究該調配物於室溫下1個月的穩定性及結果顯示對於這些條件它們是穩定的(表9及圖5)。
表9. 以WSLutein調配的Doubledyne、Retidyne及Phacodyne之分析
研究以WSLutein調配的Doubledyne之光穩定性及與DoubledyneTM(具CWSLutein)之光穩定性比較。表10及11顯示在透明與琥珀色小瓶之間的比較結果。
表10. 以WSLutein調配的Doubledyne之光穩定性,相比於DoubledyneT
M
(CWSLutein)
表11. 由CWSLutein產品(CWSDoubledyne)至WSLutein產品(WSDoubledyne)及由光曝照至無光曝照的小瓶之衰減百分率
用以驗證利用CWSLutein調配的Kemin Pharma染料之品質的規格必須確保pH及滲透壓係完全與該眼睛生理參數相容。因此,pH必須在6.0至7.4內(即,pH=6.7±0.7或pH=6.7±10.45%)及滲透壓必須在250至380mOsm/L內(即,滲透壓=315±65mOsm/L或315±20.63% mOsm/L)。
對於眼應用,雖然pH及滲透壓是這些調配物的重要特性,
但於452nm的吸收度是相關於葉黃素穩定性之最重要參數,因為它完全取決於葉黃素含量。以CWS調配的商業的Doubledyne之規格預測於452nm的吸收度必須在0.633至0.861內(即,0.861±0.228或0.861±26.50%)。欲評估光穩定性,我們考慮在條件間更嚴格的10%區間的吸收度變量,以確保我們準確地評估葉黃素穩定性。
歸納於表10及11的結果顯示,當光-曝照的透明小瓶相比於無光曝照的透明小瓶時,只有CWSDoubledyne於452nm的吸收度有顯著衰減(>10%)。從表11,因為對於任何參數未見到任何顯著衰減,WSDoubledyne可被認為是光穩定的。
屍體眼睛研究。以一很類似的WSLutein微脂體的溶液調配的Retidyne及Phacodyne,代替CWSLutein,在人屍體眼睛評估,以測定它們死的眼膜及結構的功效。結果列示於表12及顯示一對ILM的Retidyne調配物、及對前囊(anterior capsule)染色的Phacodyne(主要目標結構)之良好染色容量。
討論
有需要開發一新穎水溶性之葉黃素/玉米黃素其沒有由DSM Nutritional Products,Inc.商品化的CWSLutein之不希望的作用。目前,利用這可溶性CWSLutein製得數種染料。可惜是,經過時間顯示這可溶形式為不穩定的,在溶液中1至2日後發現沈降物,還有不利於葉黃素可分散性,主
要是由於其極剛性之多醣-相似的材料組成物(Amar I,Abraham A and Garti N.Solubilization Patterns of Lutein and Lutein Esters in Food Grade Nonionic Microemulsions.2003.J.Agric.Food Chem.51:4775-4781)。此外,維生素/膳食補充劑/醫療器材產品之製造需要能夠耐一廣範圍的製錠壓力及滅菌方案之材料,能夠用在葉黃素轉化(transformation)之成分設定重要限制。這些相同限制據信在葉黃素的生物利用性中扮演一關鍵性角色,因為所用的新穎方法必須確保這分子的釋放。
因此,需要開發一可溶於水之新穎原料,其不會沈降,能夠使葉黃素可生物利用性及阻抗蒸汽滅菌。這不僅對於專屬染料且還對於錠化的產品、醫療器材及相關食品的產品之製造者是有利。
本文敘述開發該調配物及製造方法以達到這些目的及產生WSLutein,一微脂體葉黃素(200至800nm)其顯示為穩定的及可溶於水。更且,該沈降現象比在CWSLutein中見到的不明顯。存在磷脂質、二十二酸甘油酯及一親脂性環境幫助葉黃素遞送至眼、鼻或皮膚結構內及,在口用之情況下,允許葉黃素之良好可分散性及更好吸收性。再者,存在二十二酸甘油酯,其具有高於50℃的熔點,具有調整最後結構之剛性之潛力及因此吸收性輪廓。
在以WSLutein的染料調配物(組合有台盼藍及/或亮藍)之初步測試中,這些染料經過高壓滅菌及於室溫下1個月後顯示是穩定的,如WSLutein般。又,WSLutein原料顯示於室溫下6個月是穩定的。將遵循ICH指引進行較長期穩定性研究及將有助於更好了解這原料的穩定性輪廓。對光曝照的敏感性是CWSLutein的另一不希望的特性。在光穩定性研究中,WSLutein(及以WSLutein調配的染料)顯示光穩定的及這特性還支持這原料的高品質。在製藥工業中另一重要議題是所用材料的安全性及WSLutein在視網膜細胞系(retinal cell line)中顯示沒有任何細胞毒性,其強化這新穎原料的優點。
WSLutein因此被建議用在藥品、醫療器材、及膳食補充品工業,除了它在化妝品工業用途之外,對於咀嚼錠、營養強化的飲料、發泡錠、未塗佈的錠劑、營養棒、及功能性食品具巨大潛力。
在這產品上還進行更穩定性研究,還有評估利用以
WSLutein調配的染料之安全實驗,如此可獲得註冊(細胞毒性,敏感性及刺激性(irritation)測試,以及體內功效)。
上述說明及圖式包含本發明之說明性實施例。上述本文所述的實施例及方法可以此項技術領域熟悉者的能力、經驗、及優勢為基礎而作變化。只列示以某種順序的方法步驟不會在方法步驟順序上構成任何限制。除了在申請專利範圍的範圍內如此限制之外,上述說明及圖式只解釋及描述本發明,且本發明並未受到其限制。在具有該揭露內容的技術領域中熟悉者在其之前將能夠在不偏離本發明的範疇之中作修飾及改變。
Claims (7)
- 一種獲得可溶形式之親脂分子之方法,包含下述步驟:將該親脂分子溶解於溶劑中以形成溶液,將該溶液混入形成脂質膜之液體與剛性改質劑內以形成混合物,乾燥該混合物以形成脂質膜,水合該脂質膜,均質化該水合的脂質膜以形成微脂體,及滅菌所獲得的微脂體。
- 如申請專利範圍第1項之方法,其中該親脂分子包含葉黃素晶體。
- 一種組成物,其包含含於具有脂肪塗層之微脂體內的葉黃素晶體。
- 如申請專利範圍第3項之組成物,其中該葉黃素係以0.001%至10%之濃度範圍存在。
- 如申請專利範圍第3項之組成物,其中該脂肪為二十二酸甘油酯(glyceryl behenate)。
- 一種醫藥組成物,包含負載有一定用量的葉黃素之微脂體,及含有醫藥可接受賦形劑之組成物。
- 一種原料,其係用在藥品、醫療器材、膳食補充品工業,除了化妝品工業之外,對咀嚼錠、營養強化的飲料、發泡錠、未塗佈的錠劑、營養棒、及功能性食品具有潛力。
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CN (1) | CN108697681B (zh) |
BR (1) | BR112018016468A2 (zh) |
CA (1) | CA3014616A1 (zh) |
TW (1) | TW201740926A (zh) |
WO (1) | WO2017142834A1 (zh) |
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TWI813865B (zh) * | 2020-03-20 | 2023-09-01 | 晶碩光學股份有限公司 | 含有葉黃素的隱形眼鏡用液體組成物及使用其的眼用產品 |
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KR102395996B1 (ko) * | 2019-12-30 | 2022-05-11 | (주)파이온텍 | 카로티노이드 화합물의 안정성을 개선하는 리포좀의 제조방법 및 이를 이용한 기능성 화장품 조성물 |
KR102339804B1 (ko) * | 2021-09-28 | 2021-12-15 | 주식회사 바이오뷰텍 | 분자클러스터링 상태에서 다중층으로 형성된 리포좀 구조체 안에 유효성분을 봉입하여 안정성을 더욱 높이는 제조방법 및 이를 함유하는 화장료 조성물 |
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US85919A (en) * | 1869-01-19 | Improved trunk | ||
IL94103A0 (en) | 1989-04-25 | 1991-01-31 | Nattermann A & Cie | Water-containing formulations with phospholipids,their preparation and application |
CA2120197A1 (en) * | 1993-04-02 | 1994-10-03 | Kenji Endo | Stable aqueous dispersions containing liposomes |
US7485320B2 (en) * | 2000-09-25 | 2009-02-03 | Industrial Technology Research Institute | Liposome for incorporating large amounts of hydrophobic substances |
AU2004290476A1 (en) | 2003-11-20 | 2005-06-02 | Ym Biosciences Inc. | Stable liposome compositions comprising lipophilic amine containing pharmaceutical agents |
US7446101B1 (en) * | 2003-12-12 | 2008-11-04 | Bioactives, Llc | Bioavailable carotenoid-cyclodextrin formulations for soft-gels and other encapsulation systems |
WO2005107712A1 (en) * | 2004-05-03 | 2005-11-17 | Hermes Biosciences, Inc. | Liposomes useful for drug delivery |
KR100823345B1 (ko) * | 2006-09-22 | 2008-04-17 | 한국콜마 주식회사 | 코엔자임 큐텐을 포함하는 나노크기의 리포좀 에멀젼을 담지한 실리카 및 그의 제조방법 |
AU2010200636B2 (en) | 2009-04-27 | 2015-05-28 | Katra Phytochem (India) Private Limited | A process for isolation of carotenoids from plant sources |
US20110070293A1 (en) | 2009-09-23 | 2011-03-24 | Javeri Indu | Methods for the Preparation of Liposomes Comprising Docetaxel |
CN103622912B (zh) | 2013-12-05 | 2016-02-24 | 常州金远药业制造有限公司 | 盐酸多柔比星-多西他赛或紫杉醇脂质体制剂及其制备方法 |
US9622970B2 (en) * | 2014-05-08 | 2017-04-18 | Yaguang Liu | Pharmaceutical composition containing lutein and antioxidant for treating and preventing human disease |
RU2706704C2 (ru) * | 2014-12-19 | 2019-11-20 | Кемин Индастриз, Инк. | Внутриглазная доставка биологически активных молекул с использованием ионтофореза |
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- 2017-02-13 KR KR1020187026298A patent/KR20180108829A/ko unknown
- 2017-02-13 BR BR112018016468A patent/BR112018016468A2/pt not_active Application Discontinuation
- 2017-02-13 US US15/430,755 patent/US10406117B2/en not_active Expired - Fee Related
- 2017-02-13 EP EP17753685.1A patent/EP3416636A4/en not_active Withdrawn
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- 2017-02-13 WO PCT/US2017/017646 patent/WO2017142834A1/en active Application Filing
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Cited By (1)
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TWI813865B (zh) * | 2020-03-20 | 2023-09-01 | 晶碩光學股份有限公司 | 含有葉黃素的隱形眼鏡用液體組成物及使用其的眼用產品 |
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EP3416636A1 (en) | 2018-12-26 |
WO2017142834A1 (en) | 2017-08-24 |
CN108697681B (zh) | 2022-01-25 |
EP3416636A4 (en) | 2019-10-16 |
JP2019504864A (ja) | 2019-02-21 |
BR112018016468A2 (pt) | 2018-12-26 |
CA3014616A1 (en) | 2017-08-24 |
KR20180108829A (ko) | 2018-10-04 |
US20170231913A1 (en) | 2017-08-17 |
CN108697681A (zh) | 2018-10-23 |
US10406117B2 (en) | 2019-09-10 |
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