CN112399847A - 维生素k2微胶囊及其制备方法和在制备防治心脑血管疾病的药物中的应用 - Google Patents
维生素k2微胶囊及其制备方法和在制备防治心脑血管疾病的药物中的应用 Download PDFInfo
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- CN112399847A CN112399847A CN202080002124.7A CN202080002124A CN112399847A CN 112399847 A CN112399847 A CN 112399847A CN 202080002124 A CN202080002124 A CN 202080002124A CN 112399847 A CN112399847 A CN 112399847A
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Abstract
本发明属于维生素K2技术领域,涉及一种维生素K2微胶囊及其制备方法和在制备防治心脑血管疾病的药物中的应用。所述维生素K2微胶囊含有以下重量份的组分:维生素K2 0.001~10份、多不饱和脂肪酸源5~30份、维生素E聚乙二醇琥珀酸酯0.1~10份、水相壁材50~95份和抗氧化剂0.01~10份,所述多不饱和脂肪酸源中含有ω‑6源和ω‑3源,所述抗氧化剂为水相抗氧化剂和/或油相抗氧化剂。采用本发明的方法制备得到的维生素K2微胶囊的水溶性和稳定性好、生物利用度高,能够显著提高对心脑血管疾病的预防和/或治疗效果,具有广阔的应用前景。
Description
技术领域
本发明属于维生素K2技术领域,具体涉及一种维生素K2微胶囊及其制备方法和在制备防治心脑血管疾病的药物中的应用。
背景技术
心脑血管疾病是全身性血管病变或***性血管病变在心脏和脑部的表现,其泛指由于高脂血症、血液粘稠、动脉粥样硬化、高血压等所致的心脏、大脑及全身组织发生缺血性或出血性疾病。随着人类生活水平的提高,饮食结构的改变及人口的老龄化,心脑血管疾病的发病率有逐年增多趋势。心脑血管疾病严重威胁着人类的健康,具有高患病率、高致残率和高死亡率的特点,尤其是对于50岁以上的中老年人群。目前心脑血管疾病仍然是以预防为主,主要手段是控制危险因素和抗栓。因此,开发出安全有效的预防和/或治疗心脑血管的药物及相关制剂已成为医药工作者艰巨而紧迫的任务。
维生素K2,也称甲基萘醌(Menaquinone),通常用MK来表示。它由一组化合物组成,共有14种形式,差别在于侧链的长短不一,代表性的分子是MK-4和MK-7。其中,MK-7具备功能广泛、安全性高、活性强大、半衰期长等特点,主要对细胞的生长代谢及防治心脑血管和肾脏血管的钙化起到非常重要的作用。维生素K2通过激活两种平衡体内钙的蛋白质来促进骨骼和心脏健康。美国国立卫生研究院膳食补充剂办公室评价维生素K2(MK-7)为革命性和多能性的维生素,其具有健康保健的广阔应用前景。相关研究发现,病情恶化的新冠病毒COVID-19患者缺乏充足的维生素K2,特别是全球疫情背景下公众对维生素K2及其在免疫健康和COVID-19结果中的潜在作用产生了新的兴趣。然而,天然食物中维生素K2(MK-7)的含量极低,基本无法通过食物摄取足量的维生素K2(MK-7)来满足身体的各项需求。
维生素K2是脂溶性药物,在水中的溶解度很小,因而口服给药后胃肠道消化吸收方面存在困难,生物利用度极低。另外,维生素K2对光和氧相当敏感,暴露于光下容易分解。鉴于此,即使维生素K2具有很好的保健药理作用,但如果没有提高其在水相介质中的溶解性并提高其稳定性,那它在临床上的疗效也很难达到期望值。此外,维生素K2主要是从纳豆中提取或由微生物发酵制得,人工合成难度较大。因此,亟需开发一种水溶性、稳定性以及生物利用度均更高的维生素K2产品,既能保证维生素K2在体内能够达到保健药理作用的所需浓度,又能节约原料,降低生产成本。
发明内容
本发明的目的是为了克服维生素K2水溶性和稳定性差、生物利用度低的缺陷,而提供一种能够提高维生素K2水溶性和稳定性以及生物利用度的维生素K2微胶囊及其制备方法和在制备防治心脑血管疾病的药物中应用。
本发明的发明人经过不断试验发现,将维生素K2、ω-6源/ω-3源、维生素E聚乙二醇琥珀酸酯、水相壁材和抗氧化剂按照(0.001~10):(5~30):(0.1~10):(50~95):(0.01~10)的重量比作为原料制成维生素K2微胶囊,一方面,维生素K2、ω-6和ω-3在预防和/或治疗心脑血管疾病方面具有协同效应,ω-6和ω-3能够显著提高维生素K2的生物利用度;另一方面,将维生素K2制成微胶囊,可有效解决其水溶性差的问题并改善其不稳定性,微胶囊能够有效包埋住芯材中的维生素K2,隔绝光照并避免维生素K2与空气接触,防止其迁移和被氧化,从而能够提高微胶囊中维生素K2的稳定性,再则,在维生素K2微胶囊的制备过程中,维生素E聚乙二醇琥珀酸酯(TPGS)以一定配比、分两部分分别添加于油相和水相中,可大幅度降低乳化均质压力,提高维生素K2的稳定性,这种内部依靠维生素E聚乙二醇琥珀酸酯、外部依靠微胶囊包裹的双重作用能够显著提高维生素K2的水溶性和稳定性,更有利于其生物活性的发挥。基于此,完成了本发明。
具体地,本发明提供了一种维生素K2微胶囊,其中,所述维生素K2微胶囊含有以下重量份的组分:维生素K2 0.001~10份、多不饱和脂肪酸源5~30份、维生素E聚乙二醇琥珀酸酯0.1~10份、水相壁材50~95份和抗氧化剂0.01~10份,所述多不饱和脂肪酸源中含有ω-6源和ω-3源,所述抗氧化剂为水相抗氧化剂和/或油相抗氧化剂。
进一步地,所述维生素K2微胶囊含有以下重量份的组分:维生素K2 0.005~5份、多不饱和脂肪酸源10~25份、维生素E聚乙二醇琥珀酸酯0.5~5份、水相壁材55~90份和抗氧化剂0.05~5份。
进一步地,所述维生素K2为MK-7构型。
进一步地,所述多不饱和脂肪酸源中ω-6和ω-3的质量比为(0.5~4):1,优选为(1~2):1,更优选为1.5:1。
进一步地,所述ω-3源选自DHA藻油、鱼油、亚麻籽油、紫苏籽油、低芥酸菜籽油、核桃油、花椒籽油和大豆油中的至少一种。
进一步地,所述ω-6源选自ARA油、葡萄籽油、红花籽油、大豆油、低芥酸菜籽油、核桃油、葵花籽油和芝麻油中的至少一种。
进一步地,所述水相壁材选自蛋白类化合物壁材、碳水化合物壁材和改性淀粉中的至少一种。
进一步地,所述蛋白类化合物壁材选自酪蛋白酸钠、大豆蛋白、醇溶蛋白和乳清蛋白中的至少一种。
进一步地,所述碳水化合物壁材选自***胶、白砂糖、环糊精、麦芽糊精、固体玉米糖浆和葡萄糖浆干粉中的至少一种。
进一步地,所述改性淀粉为辛烯基琥珀酸淀粉钠和/或十二烯基琥珀酸淀粉钠。
进一步地,所述水相抗氧化剂选自抗坏血酸钠、抗坏血酸和柠檬酸钠中的至少一种。
进一步地,所述油相抗氧化剂选自卵磷脂、天然VE、迷迭香提取物和抗坏血酸棕榈酸酯中的至少一种。
进一步地,所述维生素K2微胶囊还含有助流剂、矫味剂和着色剂中的至少一种。
进一步地,所述助流剂、矫味剂和着色剂的含量各自独立地为0~5重量份,优选各自独立地为0~2重量份。
本发明还提供了所述维生素K2微胶囊的制备方法,该方法包括:
(1)将水相壁材、部分维生素E聚乙二醇琥珀酸酯以及任选的水相抗氧化剂、助流剂、矫味剂和着色剂分散于水中,得到水相物料;将维生素K2、多不饱和脂肪酸源、剩余部分维生素E聚乙二醇琥珀酸酯和任选的油相抗氧化剂混合均匀,得到油相物料;所述水相物料和油相物料中维生素E聚乙二醇琥珀酸酯的重量比为(2~6):1;
(2)将所述水相物料和油相物料混合、高速剪切乳化、均质压力30~50MPa处理至油滴粒径≤100纳米的乳液,再将所得乳液喷雾干燥制成维生素K2微胶囊。
进一步地,步骤(1)中,将所述水相壁材、部分维生素E聚乙二醇琥珀酸酯以及任选的水相抗氧化剂、助流剂、矫味剂和着色剂分散于水中的方式为将水相壁材溶于35~45℃水中,在惰性气氛下超声分散得到壁材水溶液,料液以逆流循环的方式通过超声探头,之后将维生素E聚乙二醇琥珀酸酯以及任选的水相抗氧化剂、助流剂、矫味剂和着色剂加入到壁材水溶液中,在惰性气氛下混合均匀,得到水相物料。
进一步地,步骤(1)中,所述超声分散的条件包括超声功率为240~480w,超声时间为10~30min。
进一步地,步骤(1)中,将维生素K2、多不饱和脂肪酸源、剩余部分维生素E聚乙二醇琥珀酸酯和任选的油相抗氧化剂混合均匀的方式为在惰性气氛下,将维生素K2、多不饱和脂肪酸源、维生素E聚乙二醇琥珀酸酯和任选的油相抗氧化剂加热至35~50℃,保温搅拌直至各组分完全溶解,得油相物料。
进一步地,步骤(2)中,所述水相物料和油相物料的混合方式为将水相物料和油相物料以质量比(1.5~2.5):1的速度同时放料混合。
进一步地,步骤(2)中,所述喷雾干燥的条件包括喷雾进风温度为140~170℃,出风温度为80~95℃,雾化器频率为165~200Hz,冷却风温度为16~22℃,进料温度为50~60℃。
本发明还提供了由上述方法制备得到的维生素K2微胶囊。
本发明还提供了所述维生素K2微胶囊作为膳食补充剂或保健食品中的应用。
此外,本发明还提供了所述维生素K2微胶囊在制备防治心脑血管疾病的药物中的应用。
采用本发明提供的方法所得维生素K2微胶囊能够显著提高维生素K2的水溶性、稳定性以及生物利用度,能够显著提高对心脑血管疾病的预防和/或治疗效果,具有广阔的应用前景。
具体实施方式
所述维生素K2微胶囊中,所述维生素K2的含量为0.001~10重量份,具体可以为0.001、0.005、0.01、0.05、0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1、2、3、4、5、6、7、8、9、10重量份等,特别优选为0.005~5重量份。所述维生素K2可以为其14种形式中的任意一种及其组合,优选为MK-7构型,这是由于与其他构型相比,MK-7构型具有功能广泛、安全性高、活性强大、半衰期长等特点,所得维生素K2微胶囊在预防和/或治疗心脑血管疾病方面效果更显著。
所述维生素K2微胶囊中,所述多不饱和脂肪酸源的含量为5~30重量份,具体可以为5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30重量份等,特别优选为10~25重量份。所述多不饱和脂肪酸是指含有两个或两个以上双键且碳链长度为18~22个碳原子的直链脂肪酸。根据甲基端第一个双键碳原子的位置,所述多不饱和脂肪酸可分为ω-3型和ω-6型多不饱和脂肪酸。其中,所述ω-3型多不饱和脂肪酸包括α-亚麻酸(ALA)、二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)。所述ω-3源具体可以选自DHA藻油、鱼油、亚麻籽油、紫苏籽油、低芥酸菜籽油、核桃油、花椒籽油和大豆油中的至少一种。所述ω-6型多不饱和脂肪酸包括亚油酸(LA)、γ-亚麻酸(GLA)和花生四烯酸(ARA)。所述ω-6源具体可以选自ARA油、葡萄籽油、红花籽油、大豆油、低芥酸菜籽油、核桃油、葵花籽油和芝麻油中的至少一种。由于ω-3型多不饱和脂肪酸和ω-6型多不饱和脂肪酸在机体代谢过程中需要相同的酶系,导致它们之间存在一定的竞争关系,为了更适合基体吸收,所述多不饱和脂肪酸源中ω-6和ω-3的质量比优选为(0.5~4):1,更优选为(1~2):1,最优选为1.5:1。
所述维生素E聚乙二醇琥珀酸酯(TPGS)是由维生素E琥珀酸酯与聚乙二醇经酯化形成的,包括d-α-维生素E琥珀酸聚乙二醇酯(d-TPGS)和dl-α-维生素E琥珀酸聚乙二醇酯(dl-TPGS)。所述维生素E聚乙二醇琥珀酸酯拥有PEG的优点,即体内长循环、半衰期长、提高药物的细胞摄取,在药物传递***的应用中具有很大的优势。此外,维生素E聚乙二醇琥珀酸酯可抑制P-糖蛋白(P-g)的功能而促进药物吸收,并且具有抗氧化作用。所述维生素K2微胶囊中,所述维生素E聚乙二醇琥珀酸酯的含量为0.1~10重量份,具体可以为0.1、0.5、1、2、3、4、5、6、7、8、9、10重量份等,优选为0.5~5重量份。
所述维生素K2微胶囊中,所述水相壁材的含量为50~95重量份,具体可以为50、55、60、65、70、75、80、85、90、95重量份等,优选为55~90重量份。所述水相壁材可以选自蛋白类化合物壁材、碳水化合物壁材和改性淀粉中的至少一种。其中,所述蛋白类化合物壁材的具体实例包括但不限于:酪蛋白酸钠、大豆蛋白、醇溶蛋白和乳清蛋白中的至少一种。所述碳水化合物壁材的具体实例包括但不限于:***胶、白砂糖、环糊精、麦芽糊精、固体玉米糖浆和葡萄糖浆干粉中的至少一种。所述改性淀粉的具体实例包括但不限于:辛烯基琥珀酸淀粉钠和/或十二烯基琥珀酸淀粉钠。
所述维生素K2微胶囊中,所述抗氧化剂的含量为0.01~10重量份,具体可以为0.01、0.05、0.1、0.5、1、2、3、4、5、6、7、8、9、10重量份,优选为0.05~5重量份。所述抗氧化剂可以为油相抗氧化剂,也可以为水相抗氧化剂,还可以为两者的组合,其具体实例包括但不限于:卵磷脂、天然VE、迷迭香提取物、抗坏血酸棕榈酸酯、抗坏血酸钠、抗坏血酸和柠檬酸钠中的至少一种。
所述维生素K2微胶囊中还可以含有助流剂、矫味剂和着色剂中的至少一种。其中,所述助流剂、矫味剂和着色剂的含量可以各自独立地为0~5重量份,优选各自独立地为0~2重量份。所述助流剂、矫味剂和着色剂的种类均可以为本领域的常规选择,对此本领域技术人员均能知悉,在此不作赘述。
本发明提供的所述维生素K2微胶囊的制备方法包括:
(1)将水相壁材、部分维生素E聚乙二醇琥珀酸酯以及任选的水相抗氧化剂、助流剂、矫味剂和着色剂分散于水中,得到水相物料;将维生素K2、多不饱和脂肪酸源、剩余部分维生素E聚乙二醇琥珀酸酯和任选的油相抗氧化剂混合均匀,得到油相物料;所述水相物料和油相物料中维生素E聚乙二醇琥珀酸酯的重量比为(2~6):1;
(2)将水相物料和油相物料混合、高速剪切乳化、均质压力30~50MPa处理至油滴粒径≤100纳米的乳液,再将所得乳液喷雾干燥制成维生素K2微胶囊。
本发明对将所述水相壁材、部分维生素E聚乙二醇琥珀酸酯以及任选的水相抗氧化剂、助流剂、矫味剂和着色剂分散于水中的方式没有特别的限定,可以将以上几种组分按照任意顺序分散于水中。在一种优选实施方式中,所述分散的方式为将水相壁材溶于35~45℃水中,在惰性气氛下超声分散得到壁材水溶液,所述超声分散的条件包括超声功率为240~480w,超声时间为10~30min,料液以逆流循环的方式通过超声探头,之后将维生素E聚乙二醇琥珀酸酯以及任选的水相抗氧化剂、助流剂、矫味剂和着色剂加入到壁材水溶液中,在惰性气氛下混合均匀,得到水相物料。
在一种具体实施方式中,步骤(1)中,将维生素K2、多不饱和脂肪酸源、剩余部分维生素E聚乙二醇琥珀酸酯和任选的油相抗氧化剂混合均匀的方式为在惰性气氛下,将维生素K2、多不饱和脂肪酸源、维生素E聚乙二醇琥珀酸酯和任选的油相抗氧化剂加热至35~50℃,保温搅拌直至各组分完全溶解,得到油相物料。
在一种具体实施方式中,步骤(2)中,所述水相物料和油相物料的混合方式为将水相物料和油相物料以质量比(1.5~2.5):1的速度同时放料混合。
在一种具体实施方式中,步骤(2)中,所述喷雾干燥的条件包括喷雾进风温度为140~170℃,出风温度为80~95℃,雾化器频率为165~200Hz,冷却风温度为16~22℃,进料温度为50~60℃。
本发明还提供了由上述方法制备得到的维生素K2微胶囊。
本发明还提供了所述维生素K2微胶囊作为膳食补充剂或保健食品的应用。
此外,本发明还提供了所述维生素K2微胶囊在制备防治心脑血管疾病的药物中的应用。所述维生素K2微胶囊在防治心脑血管疾病中具有显著功效。所述心脑血管疾病包括高血压、高血脂、心肌梗死、动脉粥样硬化、脑梗塞等。其中,高血脂包括高胆固醇血症、高甘油三酯血症等,具体表现为血液中的总胆固醇升高、低密度脂蛋白胆固醇升高、甘油三酯升高和高密度脂蛋白胆固醇降低中的一项或多项。
以下将通过实施例对本发明进行详细描述。
实施例1
(1)原料组成:
上述亚麻籽油、大豆油和葡萄籽油组成的混合油脂中,多不饱和脂肪酸ω-6/ω-3的重量比为1.5:1。
(2)维生素K2微胶囊的制备:
将改性淀粉、固体玉米糖浆、麦芽糊精溶于110重量份40℃纯水中,在氮气气氛下超声波处理,超声功率为240w,超声处理时间为30min,料液以逆流循环的方式通过超声探头,得到壁材水溶液;再将抗坏血酸钠、0.4重量份TPGS加入到所得的壁材水溶液中,在氮气气氛下溶解、混合均匀制备成水相物料。将维生素K2、亚麻籽油、大豆油、葡萄籽油、0.1重量份TPGS、迷迭香提取物在氮气气氛下加热至40℃,保温搅拌直至各组分完全溶解,得到油相物料。接着将所得水相物料和油相物料以2:1的速度同时放料混合、10000rpm转速下剪切10分钟使体系乳化至油滴粒径≤2微米,然后进入设定压力为30MPa的高压微射流处理2次,得到油滴粒径≤100纳米的乳液;将所得乳液进行喷雾干燥,设置进料温度为50℃,进风温度为150℃,出风温度为80℃,雾化器频率为180Hz,冷却风温度为22℃,得到维生素K2微胶囊,其收率为98.7%(以维生素K2计,下同),维生素K2含量为4957ppm,油滴粒径分布D90为92nm。
实施例2
(1)原料组成:
组分 | 投料量(重量份) |
维生素K2 | 0.005 |
紫苏籽油 | 5 |
核桃油 | 2 |
低芥酸菜籽油 | 3 |
TPGS | 1(0.8水相、0.2油相) |
抗坏血酸钠 | 0.02 |
抗坏血酸棕榈酸酯 | 0.03 |
改性淀粉capsul TA | 30 |
葡萄糖浆干粉 | 25 |
麦芽糊精 | 33.945 |
上述紫苏籽油、核桃油、低芥酸菜籽油组成的混合油脂中,多不饱和脂肪酸ω-6/ω-3的重量比为0.8:1。
(2)维生素K2微胶囊的制备:
将改性淀粉、葡萄糖浆干粉、麦芽糊精溶于110重量份40℃纯水中,在氮气气氛下超声波处理,超声功率为300w,超声处理时间为25min,料液以逆流循环的方式通过超声探头,得到壁材水溶液;再将抗坏血酸钠、0.8重量份TPGS加入到所得的壁材水溶液中,在氮气气氛下溶解、混合均匀制备成水相物料。将维生素K2、紫苏油、核桃油、低芥酸菜籽油、0.2重量份TPGS、抗坏血酸棕榈酸酯在氮气气氛下加热至45℃,保温搅拌直至各组分完全溶解,得到油相物料。接着将所得水相溶液和油相物料以2:1的速度同时放料混合、10000rpm转速下剪切10分钟使体系乳化至油滴粒径≤2微米,然后进入设定压力为35MPa的高压微射流处理2次,得到油滴粒径≤100纳米的乳液;将所得乳液进行喷雾干燥,设置进料温度为50℃,进风温度为160℃,出风温度为80℃,雾化器频率为180Hz,冷却风温度为18℃,得到维生素K2微胶囊,其收率为99.0%,维生素K2含量为4965ppm,油滴粒径分布D90为90nm。
实施例3
(1)原料组成:
组分 | 投料量(重量份) |
维生素K2 | 0.005 |
DHA藻油 | 2 |
鱼油 | 2 |
ARA油 | 6 |
TPGS | 1(0.8水相、0.2油相) |
抗坏血酸钠 | 0.01 |
柠檬酸钠 | 0.01 |
迷迭香提取物 | 0.02 |
卵磷脂 | 0.02 |
乳清蛋白 | 35 |
白砂糖 | 20 |
麦芽糊精 | 33.935 |
上述DHA藻油、鱼油、ARA油组成的混合油脂中,多不饱和脂肪酸ω-6/ω-3的重量比为2.5:1。
(2)维生素K2微胶囊的制备:
将乳清蛋白、白砂糖、麦芽糊精溶于120重量份45℃纯水中,在氮气气氛下超声波处理,超声功率为480w,超声处理时间为10min,料液以逆流循环的方式通过超声探头,得到壁材水溶液;再将抗坏血酸钠、柠檬酸钠、0.8重量份TPGS加入到所得的壁材水溶液中,在氮气气氛下溶解、混合均匀制备成水相物料。将维生素K2、DHA藻油、鱼油、ARA油、0.2重量份TPGS、迷迭香提取物、卵磷脂在氮气气氛下加热至45℃,保温搅拌直至各组分完全溶解,得到油相物料。接着将所得水相物料和油相物料以2:1的速度同时放料混合、10000rpm转速下剪切10分钟使体系乳化至油滴粒径≤2微米,然后进入设定压力为30MPa的高压微射流处理2次,得到油滴粒径≤100纳米的乳液;将所得乳液进行喷雾干燥,设置进料温度为50℃,进风温度为155℃,出风温度为85℃,雾化器频率为180Hz,冷却风温度为18℃,得到维生素K2微胶囊,其收率为98.9%,维生素K2含量为4958ppm,油滴粒径分布D90为89nm。
实施例4
(1)原料组成:
组分 | 投料量(重量份) |
维生素K2 | 0.005 |
核桃油 | 4 |
亚麻籽油 | 1 |
芝麻油 | 4 |
紫苏籽油 | 1 |
TPGS | 1.5(1.2水相、0.3油相) |
抗坏血酸钠 | 0.02 |
迷迭香提取物 | 0.02 |
抗坏血酸棕榈酸酯 | 0.02 |
***胶SD | 35 |
***胶FT | 18 |
白砂糖 | 12 |
麦芽糊精 | 23.435 |
上述核桃油、亚麻籽油、芝麻油、紫苏籽油组成的混合油脂中,多不饱和脂肪酸ω-6/ω-3的重量比为3.5:1。
(2)维生素K2微胶囊的制备:
将***胶SD、***胶FT、白砂糖、麦芽糊精溶于110重量份45℃纯水中,在氮气气氛下超声波处理,超声功率为350w,超声处理时间为20min,料液以逆流循环的方式通过超声探头,得到壁材水溶液;再将抗坏血酸钠、1.2重量份TPGS加入到所得的壁材水溶液中,在氮气气氛下溶解、混合均匀制备成水相物料。将维生素K2、核桃油、亚麻籽油、芝麻油、紫苏油、0.3重量份TPGS、迷迭香提取物、抗坏血酸棕榈酸酯在氮气气氛下加热至45℃,保温搅拌直至各组分完全溶解,得到油相物料。接着将所得水相物料和油相物料以2:1的速度同时放料混合、10000rpm转速下剪切10分钟使体系乳化至油滴粒径≤2微米,然后进入设定压力为40MPa的高压微射流处理2次,得到油滴粒径≤100纳米的乳液;将所得乳液进行喷雾干燥,设置进料温度为55℃,进风温度为165℃,出风温度为85℃,雾化器频率为185Hz,冷却风温度为18℃,得到维生素K2微胶囊,其收率99.2%,维生素K2含量为4971ppm,油滴粒径分布D90为86nm。
实施例5
(1)原料组成:
组分 | 投料量(重量份) |
维生素K2 | 10 |
鱼油 | 5 |
DHA藻油 | 5 |
葵花籽油 | 20 |
TPGS | 5(4水相、1油相) |
抗坏血酸钠 | 2 |
抗坏血酸棕榈酸酯 | 3 |
改性淀粉12633 | 25 |
固体玉米糖浆 | 15 |
麦芽糊精 | 10 |
上述鱼油、DHA藻油、葵花籽油组成的混合油脂中,多不饱和脂肪酸ω-6/ω-3的重量比为2.1:1。
(2)维生素K2微胶囊的制备:
将改性淀粉、固体玉米糖浆、麦芽糊精溶于120重量份40℃纯水中,在氮气气氛下超声波处理,超声功率为480w,超声处理时间为10min,料液以逆流循环的方式通过超声探头,得到壁材水溶液;再将抗坏血酸钠、4重量份TPGS加入到所得的壁材溶液中,在氮气气氛下溶解、混合均匀制备成水相物料。将维生素K2、鱼油、DHA藻油、葵花籽油、1重量份TPGS、抗坏血酸棕榈酸酯在氮气气氛下加热至45℃,保温搅拌直至各组分完全溶解,得到油相物料。接着将所得水相物料和油相物料以2:1的速度同时放料混合、10000rpm转速下剪切15分钟使体系乳化至油滴粒径≤2微米,然后进入设定压力为50MPa的高压微射流处理2次,得到油滴粒径≤100纳米的乳液;将所得乳液进行喷雾干燥,设置进料温度为55℃,进风温度为170℃,出风温度为95℃,雾化器频率为180Hz,冷却风温度为16℃,得到维生素K2微胶囊,其收率为99.1%,维生素K2含量为9.94%,油滴粒径分布D90为93nm。
实施例6
(1)原料组成:
组分 | 投料量(重量份) |
维生素K2 | 10 |
紫苏籽油 | 5 |
红花籽油 | 15 |
TPGS | 5(4水相、1油相) |
抗坏血酸钠 | 2 |
抗坏血酸棕榈酸酯 | 3 |
改性淀粉T809 | 12 |
***胶SD | 18 |
白砂糖 | 13 |
麦芽糊精 | 17 |
上述紫苏籽油、红花籽油组成的混合油脂中,多不饱和脂肪酸ω-6/ω-3的重量比为4.0:1。
(2)维生素K2微胶囊的制备:
将改性淀粉、***胶SD、白砂糖、麦芽糊精溶于110重量份40℃纯水中,在氮气气氛下超声波处理,超声功率为300w,超声处理时间为25min,料液以逆流循环的方式通过超声探头,得到壁材水溶液;再将抗坏血酸钠、4重量份TPGS加入到所得的壁材水溶液中,在氮气气氛下溶解、混合均匀制备成水相物料。将维生素K2、紫苏籽油、红花籽油、1重量份TPGS、抗坏血酸棕榈酸酯在氮气气氛下加热至45℃,保温搅拌直至各组分完全溶解,得到油相物料。接着将所得水相物料和油相物料以2:1的速度同时放料混合、10000rpm转速下剪切15分钟使体系乳化至油滴粒径≤2微米,然后进入设定压力为50MPa的高压微射流处理2次,得到油滴粒径≤100纳米的乳液;将所得的乳液进行喷雾干燥,设置进料温度为55℃,进风温度为170℃,出风温度为85℃,雾化器频率为185Hz,冷却风温度为20℃,得到维生素K2微胶囊,其收率为98.8%,维生素K2含量为9.91%,油滴粒径分布D90为96nm。
实施例7
(1)原料组成:
组分 | 投料量(重量份) |
维生素K2 | 1 |
花椒籽油 | 8 |
亚麻籽油 | 2 |
葵花籽油 | 10 |
TPGS | 2(1.6水相、0.4油相) |
抗坏血酸钠 | 2 |
抗坏血酸棕榈酸酯 | 1 |
迷迭香提取物 | 1 |
***胶SD | 24 |
***胶FT | 20 |
白砂糖 | 13 |
麦芽糊精 | 16 |
上述花椒籽油、亚麻籽油、葵花籽油组成的混合油脂中,多不饱和脂肪酸ω-6/ω-3比值为3.1:1。
(2)维生素K2微胶囊的制备:
将***胶SD、***胶FT、白砂糖、麦芽糊精溶于110重量份45℃纯水中,在氮气气氛下超声波处理,超声功率为350w,超声处理时间为20min,料液以逆流循环的方式通过超声探头,得到壁材水溶液;再将抗坏血酸钠、1.6重量份TPGS加入到所得的壁材水溶液中,在氮气气氛下溶解、混合均匀制备成水相物料。将维生素K2、花椒籽油、亚麻籽油、葵花籽油、0.4重量份TPGS、迷迭香提取物、抗坏血酸棕榈酸酯在氮气气氛下加热至40℃,保温搅拌直至各组分完全溶解,得到油相物料。接着将所得水相物料和油相物料以2:1的速度同时放料混合、10000rpm转速下剪切10分钟使体系乳化至油滴粒径≤2微米,然后进入设定压力为40MPa的高压微射流处理2次,得到油滴粒径≤100纳米的乳液;将所得乳液进行喷雾干燥,设置进料温度为50℃,进风温度为165℃,出风温度为90℃,雾化器频率为190Hz,冷却风温度为20℃,得到维生素K2微胶囊,其收率为99.2%,维生素K2含量为0.99%,油滴粒径分布D90为81nm。
实施例8
(1)原料组成:
组分 | 投料量(重量份) |
维生素K2 | 1 |
DHA藻油 | 5 |
核桃油 | 2 |
葡萄籽油 | 10 |
大豆油 | 3 |
TPGS | 3(2.4水相、0.6油相) |
抗坏血酸钠 | 2 |
柠檬酸钠 | 1 |
卵磷脂 | 3 |
醇溶蛋白 | 38 |
固体玉米糖浆 | 20 |
麦芽糊精 | 12 |
上述DHA藻油、核桃油、葡萄籽油、大豆油组成的混合油脂中,多不饱和脂肪酸ω-6/ω-3的重量比为1.7:1。
(2)维生素K2微胶囊的制备:
将醇溶蛋白、固体玉米糖浆、麦芽糊精溶于110重量份40℃纯水中,在氮气气氛下超声波处理,超声功率为400w,超声处理时间为25min,料液以逆流循环的方式通过超声探头,得到壁材水溶液;再将抗坏血酸钠、柠檬酸钠、2.4重量份TPGS加入到所得的壁材水溶液中,在氮气气氛下溶解、混合均匀制备成水相物料。将维生素K2、DHA藻油、核桃油、葡萄籽油、大豆油、0.6重量份TPGS、卵磷脂在氮气气氛下加热至45℃,保温搅拌直至各组分完全溶解,得到油相物料。接着将所得水相物料和油相物料以2:1的速度同时放料混合、10000rpm转速下剪切15分钟使体系乳化至油滴粒径≤2微米,然后进入设定压力为40MPa的高压微射流处理2次,得到油滴粒径≤100纳米的乳液;将所得的乳液进行喷雾干燥,设置进料温度为50℃,进风温度为165℃,出风温度为90℃,雾化器频率为185Hz,冷却风温度为20℃,得到维生素K2微胶囊,其收率为98.9%,维生素K2含量为0.99%,油滴粒径分布D90为87nm。
实施例9
(1)原料组成:
组分 | 投料量(重量份) |
维生素K2 | 5 |
紫苏油 | 6 |
ARA油 | 2 |
芝麻油 | 3 |
大豆油 | 4 |
葵花籽油 | 5 |
TPGS | 3(2.4水相、0.6油相) |
抗坏血酸钠 | 2 |
迷迭香提取物 | 1 |
天然VE | 1 |
***胶SD | 25 |
***胶FT | 18 |
固体玉米糖浆 | 10 |
麦芽糊精 | 15 |
上述紫苏油、ARA油、芝麻油、大豆油、葵花籽油组成的混合油脂中,多不饱和脂肪酸ω-6/ω-3的重量比为2.4:1。
(2)维生素K2微胶囊的制备:
将***胶SD、***胶FT、固体玉米糖浆、麦芽糊精溶于110重量份45℃纯水中,在氮气气氛下超声波处理,超声功率为350w,超声处理时间为25min,料液以逆流循环的方式通过超声探头,得到壁材水溶液;再将抗坏血酸钠、2.4重量份TPGS加入到所得的壁材水溶液中,在氮气气氛下溶解、混合均匀制备成水相物料。将维生素K2、紫苏油、ARA油、芝麻油、大豆油、葵花籽油、0.6重量份TPGS、迷迭香提取物、天然VE在氮气气氛下加热至45℃,保温搅拌直至各组分完全溶解,得到油相物料。接着将所得水相物料和油相物料以2:1的速度同时放料混合、10000rpm转速下剪切15分钟使体系乳化至油滴粒径≤2微米,然后进入设定压力为45MPa的高压微射流处理2次,得到油滴粒径≤100纳米的乳液;将所得乳液进行喷雾干燥,设置进料温度为55℃,进风温度为170℃,出风温度为85℃,雾化器频率为180Hz,冷却风温度为22℃,得到维生素K2微胶囊,其收率98.9%,维生素K2含量为4.94%,油滴粒径分布D90为89nm。
实施例10
(1)原料组成:
组分 | 投料量(重量份) |
维生素K2 | 5 |
DHA藻油 | 10 |
ARA油 | 15 |
TPGS | 5(4水相、1油相) |
抗坏血酸钠 | 2 |
迷迭香提取物 | 1 |
抗坏血酸棕榈酸酯 | 2 |
改性淀粉capsul TA | 25 |
固体玉米糖浆 | 18 |
麦芽糊精 | 17 |
上述DHA藻油、ARA油组成的混合油脂中,多不饱和脂肪酸ω-6/ω-3的重量比为1.5:1。
(2)维生素K2微胶囊的制备:
将改性淀粉、固体玉米糖浆、麦芽糊精溶于110重量份45℃纯水中,在氮气气氛下超声波处理,超声功率为300w,超声处理时间为30min,料液以逆流循环的方式通过超声探头,得到壁材水溶液;再将抗坏血酸钠、4重量份TPGS加入到所得的壁材水溶液中,在氮气气氛下溶解、混合均匀制备成水相物料。将维生素K2、DHA藻油、ARA油、1重量份TPGS、迷迭香提取物、抗坏血酸棕榈酸酯在氮气气氛下加热至40℃,保温搅拌直至各组分完全溶解,得到油相物料。接着将所得水相物料和油相物料以2:1的速度同时放料混合、10000rpm转速下剪切10分钟使体系乳化至油滴粒径≤2微米,然后进入设定压力为50MPa的高压微射流处理2次,得到油滴粒径≤100纳米的乳液;将所得乳液进行喷雾干燥,设置进料温度为50℃,进风温度为170℃,出风温度为90℃,雾化器频率为180Hz,冷却风温度为16℃,得到维生素K2微胶囊,其收率为99.0%、维生素K2含量为4.97%,油滴粒径分布D90为85nm。
实施例11
按照实施例1的方法制备维生素K微胶囊,不同的是,将亚麻籽油、大豆油和葡萄籽油的用量分别调整为8重量份、1重量份和1重量份以使得多不饱和脂肪酸油脂ω-6/ω-3的重量比为0.2:1,其余条件与实施例1相同,得到参比维生素K2微胶囊,其收率为98.9%,维生素K2含量为4959ppm,油滴粒径分布D90为91nm。
实施例12
按照实施例1的方法制备维生素K微胶囊,不同的是,将亚麻籽油、大豆油和葡萄籽油的用量分别调整为2重量份、2重量份和6重量份以使得多不饱和脂肪酸油脂ω-6/ω-3的重量比为5:1,其余条件与实施例1相同,得到参比维生素K2微胶囊,其收率为98.6%,维生素K2含量为4955ppm,油滴粒径分布D90为94nm。
对比例1
对比例1的配方组成与实施例1相同,制备步骤上TPGS全部添加于水相中,其余条件同实施例1,得到参比维生素K2微胶囊,其收率为94.3%,维生素K2含量为4912ppm,油滴粒径分布D90为183nm。
对比例2
对比例2的配方组成与实施例1相同,制备步骤上TPGS全部添加于油相中,其余条件同实施例1,得到参比维生素K2微胶囊,其收率为94.1%,维生素K2含量为4906ppm,油滴粒径分布D90为167nm。
对比例3
按照实施例1的方法制备维生素K2微胶囊,不同的是,将TPGS采用相同重量份的月桂酸单甘酯替代,其余条件与实施例1相同,得到参比维生素K2微胶囊,其收率为91.2%,维生素K2含量为4869ppm,油滴粒径分布D90为202nm。
对比例4
按照实施例1的方法制备维生素K2微胶囊,不同的是,将多不饱和脂肪酸源(亚麻籽油、大豆油、葡萄籽油)采用相同重量份的MCT(中链甘油三酯,饱和脂肪酸)替代,其余条件与实施例1相同,得到参比维生素K2微胶囊,其收率为98.8%,维生素K2含量为4957ppm,油滴粒径分布D90为93nm。
对比例5
按照实施例1的方法制备维生素K2微胶囊,不同的是,将维生素K2采用相同重量份的MCT(中链甘油三酯,饱和脂肪酸)替代,其余条件与实施例1相同,得到参比维生素K2微胶囊,油滴粒径分布D90为89nm。
测试例1:维生素K2微胶囊的稳定性测定
(1)样品
样品1:实施例1;
样品2:实施例11;
样品3:实施例12;
对照品1:对比例1;
对照品2:对比例2;
对照品3:对比例3;
对照品4:维生素K2(VK2)原料。
(2)测试方法
将样品和对照品分别装入密封无色透明的小瓶中,分别置于4500Lx光照强度照射、充氧灌装(25℃)、60℃(恒温箱)条件下放置15天,分别于0天、5天、10天、15天取样,用USP方法测定VK2含量,考察光照、氧气、温度条件对VK2标示含量(%)的影响,结果如表1所示。
表1光照、氧气、温度条件对VK2稳定性的影响
表1的结果表明,本发明所制备的维生素K2微胶囊在光照、氧气、高温加速老化条件下,VK2标示含量基本没有变化,VK2未出现明显破坏,说明本发明所制备的维生素K2微胶囊具有较好的稳定性,能够降低光照、氧气、高温对其性质的影响,产品保质期良好。
测试例2:维生素K2微胶囊的水分散溶解性能测定
(1)样品
实施例1~12制备的维生素K2微胶囊(代号为:Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10、Y11、Y12);
对照品1(代号为DY1):购自上海某生物科技公司的2000ppm水溶性维生素K2微胶囊;
对照品2(代号为DY2):购自广东某医药科技公司的2000ppm水溶性维生素K2微胶囊;
对照品3(代号为DY3):对比例1制备的参比维生素K2微胶囊;
对照品4(代号为DY4):对比例2制备的参比维生素K2微胶囊;
对照品5(代号为DY5):对比例3制备的参比维生素K2微胶囊;
对照品6(代号为DY6):对比例4制备的参比维生素K2微胶囊;
对照品7(代号为DY7):对比例5制备的参比维生素K2微胶囊。
(2)测试方法
室温下,在100mL烧杯中加入50mL 25℃的水,静置至水中无气泡、水面平稳后,取样品、对照品各1.00g,从烧杯中央上方相同位置迅速倒入水中,记录在水中分散溶解时间,即样品全部湿润、下沉到杯底的时间,所得结果见表2。表2的结果表明,本发明所得的维生素K2微胶囊能够在水中快速分散溶解,具有较好的水分散性。
表2各样品微胶囊在水中分散溶解时间
测试例3:维生素K2微胶囊的降低血脂功能测试
(1)原理
用高胆固醇和脂类饲料喂养动物可形成脂代谢紊乱动物模型,再给予动物受试样品,可检测受试样品对高血脂症的影响,并可判定受试样品对脂质和脂蛋白的吸收、脂质的降解或***产生的影响。
(2)仪器及试剂
解剖器械,分光光度计,自动生化分析仪,胆固醇、胆盐、血清总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)测定试剂盒。
(3)动物选择及饲料
选取健康成年雄性SD大鼠,体重为150~200g,采用完全随机设计将大鼠随机每10只分为一组。
高脂饲料组:78.8wt%基础饲料、1wt%胆固醇、10wt%蛋白粉、10wt%猪油、0.2wt%胆盐。
标准饲料组:基础饲料。
(4)样品
样品1:实施例1制备的维生素K2微胶囊;
样品2:实施例2制备的维生素K2微胶囊;
样品3:实施例3制备的维生素K2微胶囊;
样品4:实施例4制备的维生素K2微胶囊;
样品5:实施例11制备的维生素K2微胶囊;
样品6:实施例12制备的维生素K2微胶囊;
对照品1:对比例4制备的维生素K2微胶囊。
对照品2:对比例5制备的维生素K2微胶囊。
(5)方法
试验设置10组,第1组为高脂饮食的对照组(给予高脂饲料),第2组为标准饮食组(给予标准饲料),其余各组分别每天给予高脂饮食的同时经口灌胃给予样品1~6和对照品1~2制备的维生素K2微胶囊,每天3次,试验时间为30天。
(6)实验步骤
在实验环境下对大鼠饲喂基础饲料观察10天,然后取尾血,测定血清总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)水平。根据TC水平,随机分成10组,按上述(5)中所述的方法进行试样,定期称量体重,试验结束后禁食16小时,测血清中TC、TG、HDL-C水平。结果见表3所示。
表3总胆固醇(mg/dL)测试结果
表4血清甘油三酯(TG)测试结果
表5血清高密度脂蛋白胆固醇(HDL-C)测试结果
从表3~表5的结果可以看出,本发明制得的维生素K2微胶囊能够有效降低大鼠血清中总胆固醇(TC)和甘油三酯(TG)水平,并且能够显著提高高密度脂蛋白胆固醇(HDL-C)水平。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在不脱离本发明的原理和宗旨的情况下在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (17)
1.一种维生素K2微胶囊的制备方法,其特征在于,所述维生素K2微胶囊含有以下重量份的组分:维生素K2 0.001~10份、多不饱和脂肪酸源5~30份、维生素E聚乙二醇琥珀酸酯0.1~10份、水相壁材50~95份、抗氧化剂0.01~10份、任选的助流剂0~5重量份、任选的矫味剂0~5重量份和任选的着色剂0~5重量份,所述多不饱和脂肪酸源中含有ω-6源和ω-3源,所述多不饱和脂肪酸源中ω-6和ω-3的质量比为(0.5~4):1,所述抗氧化剂为水相抗氧化剂和/或油相抗氧化剂,该方法包括:
(1)将水相壁材、部分维生素E聚乙二醇琥珀酸酯以及任选的水相抗氧化剂、助流剂、矫味剂和着色剂分散于水中,得到水相物料;将维生素K2、多不饱和脂肪酸源、剩余部分维生素E聚乙二醇琥珀酸酯和任选的油相抗氧化剂混合均匀,得到油相物料;所述水相物料和油相物料中维生素E聚乙二醇琥珀酸酯的重量比为(2~6):1;
(2)将所述水相物料和油相物料混合、高速剪切乳化、均质压力30~50MPa处理至油滴粒径≤100纳米的乳液,再将所得乳液喷雾干燥制成维生素K2微胶囊。
2.根据权利要求1所述的维生素K2微胶囊的制备方法,其特征在于,步骤(1)中,将所述水相壁材、部分维生素E聚乙二醇琥珀酸酯以及任选的水相抗氧化剂、助流剂、矫味剂和着色剂分散于水中的方式为将水相壁材溶于35~45℃水中,在惰性气氛下超声分散得到壁材水溶液,料液以逆流循环的方式通过超声探头,之后将维生素E聚乙二醇琥珀酸酯以及任选的水相抗氧化剂、助流剂、矫味剂和着色剂加入到壁材水溶液中,在惰性气氛下混合均匀,得到水相物料。
3.根据权利要求2所述的维生素K2微胶囊的制备方法,其特征在于,步骤(1)中,所述超声分散的条件包括超声功率为240~480w,超声时间为10~30min。
4.根据权利要求1所述的维生素K2微胶囊的制备方法,其特征在于,步骤(1)中,将维生素K2、多不饱和脂肪酸源、剩余部分维生素E聚乙二醇琥珀酸酯和任选的油相抗氧化剂混合均匀的方式为在惰性气氛下,将维生素K2、多不饱和脂肪酸源、维生素E聚乙二醇琥珀酸酯和任选的油相抗氧化剂加热至35~50℃,保温搅拌直至各组分完全溶解,得到油相物料。
5.根据权利要求1所述的维生素K2微胶囊的制备方法,其特征在于,步骤(2)中,所述水相物料和油相物料的混合方式为将水相物料和油相物料以质量比(1.5~2.5):1的速度同时放料混合。
6.根据权利要求1所述的维生素K2微胶囊的制备方法,其特征在于,步骤(2)中,所述喷雾干燥的条件包括喷雾进风温度为140~170℃,出风温度为80~95℃,雾化器频率为165~200Hz,冷却风温度为16~22℃,进料温度为50~60℃。
7.根据权利要求1所述的维生素K2微胶囊的制备方法,其特征在于,所述维生素K2微胶囊含有以下重量份的组分:维生素K2 0.005~5份、多不饱和脂肪酸源10~25份、维生素E聚乙二醇琥珀酸酯0.5~5份、水相壁材55~90份、抗氧化剂0.05~5份、助流剂0~2重量份、矫味剂0~2重量份和着色剂0~2重量份。
8.根据权利要求1所述的维生素K2微胶囊的制备方法,其特征在于,所述维生素K2为MK-7构型。
9.根据权利要求1所述的维生素K2微胶囊的制备方法,其特征在于,所述多不饱和脂肪酸源中ω-6和ω-3的质量比为(1~2):1。
10.根据权利要求9所述的维生素K2微胶囊的制备方法,其特征在于,所述多不饱和脂肪酸源中ω-6和ω-3的质量比为1.5:1。
11.根据权利要求1所述的维生素K2微胶囊的制备方法,其特征在于,所述ω-3源选自DHA藻油、鱼油、亚麻籽油、紫苏籽油、低芥酸菜籽油、核桃油、花椒籽油和大豆油中的至少一种;所述ω-6源选自ARA油、葡萄籽油、红花籽油、大豆油、低芥酸菜籽油、核桃油、葵花籽油和芝麻油中的至少一种。
12.根据权利要求1所述的维生素K2微胶囊的制备方法,其特征在于,所述水相壁材选自蛋白类化合物壁材、碳水化合物壁材和改性淀粉中的至少一种。
13.根据权利要求12所述的维生素K2微胶囊的制备方法,其特征在于,所述蛋白类化合物壁材选自酪蛋白酸钠、大豆蛋白、醇溶蛋白和乳清蛋白中的至少一种;所述碳水化合物壁材选自***胶、白砂糖、环糊精、麦芽糊精、固体玉米糖浆和葡萄糖浆干粉中的至少一种;所述改性淀粉为辛烯基琥珀酸淀粉钠和/或十二烯基琥珀酸淀粉钠。
14.根据权利要求1所述的维生素K2微胶囊的制备方法,其特征在于,所述水相抗氧化剂选自抗坏血酸钠、抗坏血酸和柠檬酸钠中的至少一种;所述油相抗氧化剂选自卵磷脂、天然VE、迷迭香提取物和抗坏血酸棕榈酸酯中的至少一种。
15.由权利要求1~14中任意一项所述的方法制备得到的维生素K2微胶囊。
16.权利要求15所述的维生素K2微胶囊作为膳食补充剂或保健食品的应用。
17.权利要求15所述的维生素K2微胶囊在制备防治心脑血管疾病的药物中的应用。
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