WO2010102508A1 - 制备低粘度高流动性类胡萝卜素油悬浮液的方法及其应用 - Google Patents

制备低粘度高流动性类胡萝卜素油悬浮液的方法及其应用 Download PDF

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WO2010102508A1
WO2010102508A1 PCT/CN2010/000262 CN2010000262W WO2010102508A1 WO 2010102508 A1 WO2010102508 A1 WO 2010102508A1 CN 2010000262 W CN2010000262 W CN 2010000262W WO 2010102508 A1 WO2010102508 A1 WO 2010102508A1
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carotenoid
oil
crystal
content
crystals
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PCT/CN2010/000262
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English (en)
French (fr)
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许新德
魏国华
项学兵
邵斌
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浙江医药股份有限公司新昌制药厂
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Priority to US13/255,271 priority Critical patent/US8748495B2/en
Priority to EP10750304.7A priority patent/EP2407153B1/en
Publication of WO2010102508A1 publication Critical patent/WO2010102508A1/zh

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A23L5/40—Colouring or decolouring of foods
    • A23L5/42—Addition of dyes or pigments, e.g. in combination with optical brighteners
    • A23L5/43—Addition of dyes or pigments, e.g. in combination with optical brighteners using naturally occurring organic dyes or pigments, their artificial duplicates or their derivatives
    • A23L5/44—Addition of dyes or pigments, e.g. in combination with optical brighteners using naturally occurring organic dyes or pigments, their artificial duplicates or their derivatives using carotenoids or xanthophylls
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention relates to the field of biochemical industry, in particular to the purpose of purifying carotenoids, especially natural carotenoids, through a series of physical processes, thereby achieving the purpose of improving the fluidity of the oil suspension.
  • Carotenoids are widely found in nature. In 1831, Wachenroder crystallized carbohydrates for the first time from carrot roots and named them as “carotene”. Later, Berzelius isolated yellow leaves from autumn leaves. Polar pigment, and named "lutein”; With the development of biophysical technology, a series of natural pigments were isolated by chromatography and named “carotenoids”. They have a common chemical structural feature, and the center of the molecule is a polyisoprene long chain with polyene bonds.
  • carotenoid groups are a hydrocarbon carotenoid which does not contain an oxygen atom in a molecule.
  • a hydrocarbon carotenoid which does not contain an oxygen atom in a molecule is called a carotenoid group; a derivative containing an oxygen functional group (such as a hydroxyl group, an epoxy group, a methoxy group, a ketone group, a hydroxyl group, etc.) and an ester thereof in the molecule It is called the lutein family.
  • beta-carotene can be fully synthesized, or obtained by fermentation or culture of salt algae.
  • lycopene may be derived from natural sources such as from tomato or fermented, or fully synthetic; lutein is an exception in these carotenoids, due to structural asymmetry, currently It is only synthesized from plants and is not synthesized at high cost.
  • carotenoids are similar in the upper part of the molecular structure and are a class of hydrocarbons and their oxidized derivatives. They are composed of eight isoprenoid units, but there are subtle differences in the six-terminal six-membered ring.
  • the presence of multiple conjugated double bond chromophores in the molecular structure of carotenoids not only gives them a unique absorption region (blue region) in the ultraviolet-visible region, so their crystals or solutions have a very brilliant red under visible light. , orange or yellow, depending on the concentration, the color displayed shows a certain change.
  • Carotenoids have long been considered a class of pigments, and the autumn leaves and the colorful animals in nature give an unparalleled aesthetic to humans.
  • these conjugated double bonds also make carotenoids a good free radical quencher, have strong antioxidant activity, can effectively block the chain free radical reaction in cells, and thus have many unique and important Physiological function.
  • beta-carotene which is a good vitamin A based on the amount of vitamin A in the body
  • beta-carotene can be automatically decomposed to supplement vitamin A deficiency.
  • Lutein and zeaxanthin are isomers, the only difference being that the position of a double bond on one of the six-membered ring ends is different. They are the only carotenoids present on the retina of the human eye, and they are selective. Deposition on the macula In the area and the entire retina, the density around the fovea of the macula is the highest, and the peripheral part of the retina is gradually reduced.
  • Lycopene has a good effect on the prevention and treatment of prostate diseases. Astaxanthin also has important anti-tumor and cancer-preventing effects. This is why many epidemiological studies have confirmed that regular and regular consumption of carotenoid-containing fruits and vegetables can reduce the risk of chronic diseases, including cardiovascular disease, while also having the beneficial effect of preventing cancer.
  • the reason for the low fluidity of the oil suspension is mainly due to the fact that some fat-soluble fibers and phospholipids are difficult to remove during the purification of natural carotenoids. These small amounts or even traces of fat-soluble fibers and phospholipid impurities can cause carotenoid oil suspensions. The viscosity increases ten or even hundreds of times, reducing the fluidity of the product. However, to date, methods for reducing or removing a small amount of fat-soluble fibers and phospholipids present in natural carotenoids have not been disclosed.
  • the present invention seeks to reduce or remove a small amount of fat-soluble fibers and phospholipids present in carotenoid crystals prior to preparing a carotenoid oil suspension, in order to reduce the viscosity of the carotenoid oil suspension, enhance its fluidity, and, further, increase The content of carotenoids in oil suspensions. Summary of the invention
  • the present invention relates to a process for preparing a low viscosity, high flow, carotenoid oil suspension.
  • a process for preparing a low viscosity, high flow, carotenoid oil suspension By removing residual fat-soluble cellulose and phospholipids as much as possible during the preparation of carotenoid crystals, the viscosity of these carotenoid oil suspensions is greatly reduced, and low-viscosity and high-flow oil suspensions are not only beneficial in It is easy to handle and fill evenly when preparing soft capsules, and can increase the content of active ingredients such as carotenoids in oil suspensions, and reduce transportation and other production costs.
  • a method of preparing a low viscosity, high flow, carotenoid oil suspension comprises the steps of:
  • the carotenoid crystal is sufficiently ground and mixed with vegetable oil, or the carotenoid crystal is mixed with the vegetable oil, and then the vegetable oil is replenished to obtain a low-viscosity and high-flowing carotenoid oil suspension.
  • carotenoid crystals especially carotenoid crystals from natural sources (including extraction from plants and fermentation), without special treatment, there are often a small amount of fat-soluble cellulose and phospholipids.
  • the key is to find a A method suitable for industrial production.
  • the invention aims at the characteristics of cellulose and phospholipids, and conveniently removes these impurities in a targeted manner, thereby increasing the content of carotenoids, and more importantly, reducing the viscosity of the oil suspension when preparing the corresponding carotenoid oil suspension. Improve its liquidity.
  • carotenoids especially natural carotenoids are generally extracted with linear hydrocarbons such as n-hexane, n-butyl hydrazine, dichloromethane, chloroform, or ethyl acetate, isobutyl acetate, etc.
  • linear hydrocarbons such as n-hexane, n-butyl hydrazine, dichloromethane, chloroform, or ethyl acetate, isobutyl acetate, etc.
  • solvents are often non-polar or weakly polar, but are extracted in solution.
  • a small amount of fat-soluble cellulose is also extracted during the process, so in the subsequent process, the fat-soluble cellulose is removed by a relatively strong organic solvent.
  • a strong polar organic solvent tetrahydrofuran which is highly soluble in carotenoids and poor in solubility in cellulose is selected to remove fat-soluble cellulose in carotenoid crystals.
  • the carotenoid is dissolved in acetone or methyl ethyl ketone, and the carotenoid crystals are removed by filtration. A small amount of phospholipid present.
  • the carotenoid crystals from which the fat-soluble fibers and phospholipids are removed are converted into fine powder by a certain micro-grinding measure, and the fine powder and the vegetable oil are mixed to obtain a high-content, fluidized carotenoid oil suspension, which is convenient for subsequent Additions in food or pharmaceutical production.
  • the ratio of the volume amount (ml) of tetrahydrofuran to the initial charge weight (g) of the carotenoid crystal in the step (1) is 5 to 25: lo; the carotenoid crystal is mixed with tetrahydrofuran, and the temperature is raised to reflux temperature with stirring. Dissolved at 50 to 70 ° C, the dissolution time is 0.5 to 2.0 hr.
  • the ratio of the volume amount (ml) of the ketone solvent to the initial charge weight (g) of the carotenoid crystal in the step (2) is 20 to 80 : 1, and the ketone solvent is acetone or methyl ethyl ketone;
  • the concentrate is mixed with a ketone solvent, and heated to a reflux temperature of 60 to 80 C to dissolve, and the dissolution time is 0.5 to 2.0 hr.
  • the ketone solvent in the mother liquor is concentrated to dryness, and the volume (ml) of anhydrous ethanol is added.
  • the ratio of the initial charge weight (g) of the carotenoid crystal is 0.1-5: lo
  • the vegetable oil in the step (3) is sunflower oil, rapeseed oil, corn oil, peanut oil, soybean oil, sesame oil, cottonseed oil, safflower oil, camellia seed oil, and One or more of olive oil; Carotenoid crystals are ground by ultrafine grinding, ball milling, or jet milling.
  • the carotenoid oil content in the carotenoid oil suspension is from 10.0 to 45.0 wt.%
  • the carotenoid oil suspension has good flow properties at 5 to 25 ° C, and No additional heating steps are required for application.
  • the carotenoid crystal is a beta-carotene crystal, an astaxanthin crystal, a canthaxanthin crystal, a lutein crystal, a zeaxanthin crystal, or a lycopene crystal.
  • the carotenoid crystals are either obtained by total chemical synthesis, or extracted from plant material, or prepared by fermentation.
  • the carotenoid crystal in the step (1) has a UV content of 50.0% to 100.0 wt.%, a phosphorus content of 0.1% to 4.5 wt.%, and a burning residue of 0.01% to 3.0 wt.%.
  • the carotenoid crystal in the step (2) has a UV content of 56.1 to 99.8 wt.%, a phosphorus content of 0.01 to 1.0 wt.%, and a burning residue of 0.01 to 1.0 wt.%.
  • the present invention also provides the use of the low viscosity high flow carotenoid oil suspension for the preparation of foods, dietary supplements and pharmaceuticals.
  • the specific preparation process of the method of the present invention is specifically described as follows: mixing the carotenoid with 5-25 times tetrahydrofuran, stirring and heating to reflux temperature (about 50 ⁇ 70 ° C), keeping the temperature for 0.5 ⁇ 2.0 hr, filtering, and removing a small amount.
  • the tetrahydrofuran in the mother liquor is concentrated to a thousand.
  • Re-inject 20-80 times the amount of ketone solvent such as acetone and methyl ethyl ketone in the concentrate warm to the reflux temperature, dissolve for 0.5 ⁇ 2.0 hr, remove most of the phospholipids by filtration, and concentrate the organic solvent in the mother liquor to dryness.
  • the carotenoid content in the crystal can be increased by 2 to 8 percentage points before the treatment.
  • the obtained high content of carotenoid crystals by appropriate means such as ultrafine pulverization, Ball milling, jet milling, pulverization, and evenly mixing with an appropriate amount of oil, the desired amount of oil suspension can be obtained.
  • the viscosity of the oil suspension is much smaller than the viscosity of the oil suspension corresponding to the untreated crystal.
  • the former has better fluidity, so that it has good operability when filling soft capsules, does not require additional heating and dissolution process, avoids possible decrease in content due to temperature rise, and active ingredients between individual capsules.
  • the content is uniform. detailed description
  • the tetrahydrofuran in the above mother liquid was concentrated to dryness, and 10.0 L of acetone was added thereto, and the mixture was further heated to reflux at 60 ° C for 0.5 hr, and filtered to obtain a phospholipid paste of about 14.3 g.
  • the mother liquid was concentrated to dryness, and 200 ml of absolute ethanol was added thereto, followed by filtration.
  • the refined lutein crystals were obtained. After drying, the crystals had a weight of 416 ° crystals of lutein UV content of 91.3 wt.%, a phosphorus content of 0.05 wt.%, and a burning residue of 0.03 wt.%.
  • the tetrahydrofuran in the above mother liquid was concentrated to dryness, and 12.0 L of acetone was added thereto, and the mixture was heated to 60 Torr under reflux for 0.5 hr, and filtered to obtain a phospholipid paste of about 12.4 g.
  • the mother liquid was concentrated to dryness, and 30 ml of absolute ethanol was added thereto, followed by filtration to obtain a purified product.
  • the lycopene UV content in the crystals is 56.1 wt.%
  • the phosphorus content is 0.5 wt.%
  • the ignition residue is 0.02 wt.%.
  • the tetrahydrofuran in the above mother liquid was concentrated to dryness, and 9.0 L of methyl ethyl ketone was added thereto, and the mixture was further heated to reflux at 80 ° C for 2.0 hr, and filtered to obtain a phospholipid paste of about 24.6 g, and the mother liquid was concentrated to dryness.
  • the purified natural lycopene crystals were filtered, and the crystals were dried to a weight of 401.0 g.
  • the beta-carotene UV content in the crystal was 91.5 wt.%, the phosphorus content was 1.0 wt.%, and the ignition residue was 0.5 wt.%.
  • beta-carotene oil suspension Weigh the refined beta-carotene crystal 210 g and 300 g peanut oil in a ball mill for about 1.5 hr, then add 120 g of peanut oil and mix well to obtain a beta-carotene oil suspension, wherein the beta-carotene content is 30.5. Wt.%, this oil suspension has good flow properties and is free to flow at 25 °C.
  • the tetrahydrofuran in the above mother liquid was concentrated to dryness, and 8.0 L of acetone was added thereto, and the mixture was further heated to reflux at 60 ° C for L5 hr, and filtered to obtain about 2.41 g of a phospholipid paste.
  • the mother liquid was concentrated to a thousand, and 500 ml of absolute ethanol was added thereto, followed by filtration.
  • the refined zeaxanthin crystals were obtained, and the crystals were dried and weighed 87.0 g.
  • the UV content of zeaxanthin in the crystal was 95.8 wt.%, the phosphorus content was 0.01 wt.%, and the ignition residue was 1.0 wt.%.
  • the tetrahydrofuran in the above mother liquid was concentrated to dryness, and 15.0 L of methyl ethyl ketone was added thereto, and the mixture was further heated to reflux at 80 ° C for 1.0 hr, and filtered to obtain a phospholipid paste of about 10.2 g.
  • the mother liquid was concentrated to dryness, and 100 ml of absolute ethanol was added thereto.
  • the purified natural astaxanthin crystals were filtered, and the crystals were dried to a weight of 359.0 g.
  • the astaxanthin UV content in the crystal was 99.2 wt.%, the phosphorus content was 0.01 wt.%, and the ignition residue was 0.08 wt.%.
  • the tetrahydrofuran in the above mother liquid was concentrated to dryness, and 20.0 L of methyl ethyl ketone was added thereto, and the mixture was further heated to reflux at 80 ° C for 10 hr, filtered to obtain a phospholipid paste of about 4.2 g, and the mother liquid was concentrated to dryness, and anhydrous ethanol was added thereto.
  • the purified canthaxanthin crystals are crystallized, and the crystals are dried and then heavy. The amount was 539.0 g.
  • the UV content of cantharidin in the crystal is 99.8 wt.%, the phosphorus content is 0.06 wt.%, and the burning residue is 0.01 wt.%.
  • Example 8 (Comparative Example 2)
  • Example 7 Comparative Example 1
  • Example 4 using the present invention that the zeaxanthin crystal is pretreated by the method disclosed in the present invention to ensure good flow.
  • the oil suspension content of the present invention can be increased from 14.3 wt.% (prior art) to 25.7 wt.% (invention)
  • the prior art has fluidity at 25 ° C
  • the invention has better flow properties at 5 °C.
  • Example 8 Comparative Example 2 using the prior art 2 with the embodiment 4 of the present invention that the zeaxanthin crystal is pretreated after the method disclosed in the patent to ensure good flow.
  • the oil suspension content can be increased from 17.8 wt.% (prior art) to 25.7 wt.% (invention)
  • the prior art has fluidity at 25 ° C

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Description

制备低粘度高流动性类胡萝卜素油悬浮液的方法及其应用
技术领域
本发明涉及生物化工领域， 具体地说， 涉及通过一系列物理过程 精制类胡萝卜素特别是天然来源的类胡萝卜素，从而达到提高其油悬 浮液流动性的目的。 技术背景 类胡萝卜素在自然界中广泛存在， 1831年， Wachenroder从胡萝 卜根中首次结晶分离出碳水化合物类的色素， 并以"胡萝卜素"命名； 之后， Berzelius从秋天的叶片中分离提取出黄色的极性色素， 并命名 为"叶黄素"； 随着生物物理技术的发展， 人们通过色谱方法分离出一 系列的天然色素， 并命名为"类胡萝卜素"。 它们具有共同的化学结构 特征， 分子中心都是多烯键的聚异戊二烯长链， 通过末端的环化、 氧 的加入或键的旋转及异构化等方式产生出许多衍生物。 目前， 己知的 类胡萝卜素成员大概有 600多种。 类胡萝卜素 (Carotenoids)属于类萜化合物， 是胡萝卜素 (Carotene) 和叶黄素 (Xanthophylls)两大类色素的总称。分子中不含有氧原子的碳 氢族类胡萝卜素称为胡萝卜素族； 分子中含有氧功能团 (如羟基、 环 氧基、 甲氧基、 酮基、 羟基等)的衍生物及其酯类则称为叶黄素族。 自然界存在的类胡萝卜素有数百种之多，但比较常见且数量相对 较大的主要有六种， 它们分别是 beta-胡萝卜素、 虾青素、 斑蝥黄素、 叶黄素、 玉米黄质和番茄红素等。 随着生物技术和合成技术的发展， 这六大类胡萝卜素中许多种类又存在着多种来源， 如 beta-胡萝卜素 可以是全合成， 又可通过发酵法或养殖盐藻得到， 还可从天然物如棕 榈油中提取； 番茄红素可以是天然来源如从番茄中提取或发酵得到， 也可是全合成的； 在这些类胡萝卜素中叶黄素是个例外， 由于结构上 的不对称性， 目前只有通过从植物中提取， 而不会高成本地合成。
这六种类胡萝卜素在分子结构上部较为相似，是一类碳氢化合物 及其氧化衍生物， 它们由 8个类异戊二烯单位组成， 只是在两个末端 六元环上存在细微的差别。类胡萝卜素分子结构中存在的多个共轭双 键发色基团不仅赋予了其在紫外一可见光区有着独特的吸收区 (蓝光 区)， 因而其结晶或溶液在可见光下具有十分绚丽的红、 橙或黄色， 因浓度的不同， 显示出的颜色有一定的变化。类胡萝卜素长期被认为 是一类色素， 自然界中秋天的落叶和各种斑谰色彩的动物给人类以无 与伦比的美感。同时这些共轭双键还使得类胡萝卜素成为良好的自由 基猝灭剂， 具有很强的抗氧化活性， 能有效地阻断细胞内的链式自由 基反应， 从而具有多种独特而又重要的生理功能。
类胡萝卜素中最广泛而要重要的是 beta-胡萝卜素， 它是良好的 维生素 A原根据体内维生素 A量的多少， beta-胡萝卜素可自动分解 而补充维生素 A 的不足。 叶黄素和玉米黄质是同分异构体， 其唯一 的区别在于其中一个六元环端链上一个双键的位置不同，它们是唯一 存在于人类眼视网膜上的一种类胡萝卜素，它们选择性地沉积在黄斑 区和整个视网膜， 以黄斑的中心凹周围密度为最高， 视网膜周边部分 逐渐减少。 这些黄斑色素能有效地防止视网膜上面氧化反应的发生， 对视网膜有重要的保护作用。番茄红素对前列腺疾病的预防和治疗有 很好的作用。虾青素也有重要的抗肿瘤和预防癌症的作用等。这就是 为什么许多流行病学研究证实，经常和有规律地消费含类胡萝卜素的 水果和蔬菜可减少慢性疾病， 包括心血管疾病的危险， 同时具有预防 癌症的有益效果。
因此， 营养学家极力推荐添加、预防性地摄取抗氧化剂维生素和 类胡萝卜素， 食物和药物市场因而为消费者提供大量此类"细胞保护 剂"。 目前市场上出现了各种各样的添加单一或多种类胡萝卜素的健 康食品，但人们补充类胡萝卜素更有效的方式是通过膳食补充剂的形 式摄入， 如各种片剂、 硬胶囊、 软胶囊等， 往往一粒片剂或胶囊就能 满足个人当天全部的类胡萝卜素需求量。 针对这些摄入方式的要求， 市场上也出现了多种类胡萝卜素剂型，如适于直接压片或套硬胶囊的 富含 beta-胡萝卜素的微粒 CarolBeta®, CaroCare®, 富含叶黄素的微 粒 CarolGold®, FloraGlo®, 富含玉米黄质的微粒 CarolZea®, 富含 番茄红素的 Redivivo®等； 也有一些适于套软胶囊的类胡萝卜素的油 悬浮液， 但对这些类胡萝卜素特别是天然来源， 包括发酵法来源和植 物或藻类提取来源天然类胡萝卜素的油悬浮液往往存在着以下问题： 要么这些油悬浮液流动性好但其中有效成分的含量较低；要么油悬浮 液中类胡萝卜素含量较高， 但是它们的粘度很高， 流动性较差。 差的 流动性会在制剂生产过程中带来很大的麻烦，一方面可能会造成在软 胶囊中填充不均匀，另一方面为了降低其粘度，要求对油悬浮液加热， 这势必增加新的操作步骤，更重要的是加热过程可能使类胡萝卜素有 一定的化学或热降解， 从而有不希望的损失。
造成油悬浮液流动性低的原因主要是因为在天然类胡萝卜素的 提纯过程中一些脂溶性纤维和磷脂较难以去除，这些少量甚至微量的 脂溶性纤维和磷脂杂质会使类胡萝卜素油悬浮液的粘度成十几倍甚 至几百倍地增加， 降低产品的流动性。 然而， 迄今为止， 尚未有披露 减少或去除天然类胡萝卜素中存在的少量脂溶性纤维和磷脂的方法。
本发明力图在制备类胡萝卜素油悬浮液之前减少或去除类胡萝 卜素晶体中存在的少量的脂溶性纤维和磷脂，以便降低类胡萝卜素油 悬浮液的粘度， 增强其流动性， 更进一步地， 可以提高油悬浮液中类 胡萝卜素的含量。 发明内容
本发明涉及一种制备低粘度高流动性的类胡萝卜素油悬浮液的 方法。通过在类胡萝卜素晶体的制备过程中尽量地去除残留的脂溶性 纤维素和磷脂类， 从而极大地降低了这些类胡萝卜素油悬浮液的粘 度，低粘度高流动性的油悬浮液不仅有利于在制备软胶囊时易于操作 且填充均匀， 而且可以提高油悬浮液中类胡萝卜素等有效成分的含 量， 降低运输及其它生产费用。
根据本发明的一方面， 制备低粘度高流动性的类胡萝卜素油悬浮 液的方法包括如下步骤：
( 1 ) 将类胡萝卜素晶体与四氢呋喃混合， 搅拌升温至回流温度 50~70°C溶解， 过滤去除脂溶性纤维素，将母液中四氢呋喃浓缩至干， 得到浓缩物；
(2)将浓缩物与酮类溶剂混合， 升温至回流温度 60〜80°C溶解， 过滤去除不溶性磷脂， 将母液中酮类溶剂浓缩至干， 加入无水乙醇在 室温下搅拌结晶、 过滤， 通过真空干燥得到类胡萝卜素晶体；
(3 ) 将类胡萝卜素晶体充分研磨后与植物油混合、 或类胡萝卜 素晶体与植物油混合研磨后再补充植物油，得到低粘度高流动性类胡 萝卜素油悬浮液。
对于类胡萝卜素晶体，特别是天然来源 (包括从植物中提取和发酵 法生产)的类胡萝卜素晶体， 不经过特殊的处理， 其中往往存在着少 量的脂溶性纤维素和磷脂，这些微量杂质的存在对类胡萝卜素油浮液 的粘度会造成很大的影响，所以在制备油悬浮液前尽可能地去除多余 的脂溶性纤维素和磷脂对提高其流动性是十分必须的，关键是要求找 到一种适于工业化生产的方法。本发明针对纤维素和磷脂的特性， 比 较方便地针对性地去除这些杂质， 从而提高类胡萝卜素的含量， 更重 要的是在制备相应的类胡萝卜素油悬浮液时能降低油悬浮液的粘度， 提高其流动性。
具体地说， 就是在制备油悬浮液前通过一系列方便的物理过程去 除类胡萝卜素中大部分脂溶性纤维性和磷脂类等杂质，提高类胡萝卜 素晶体的含量。这些类胡萝卜素晶体是经过提纯重结晶处理的， 其中 有效成分含量在 90%左右。
首先， 考虑到类胡萝卜素， 特别是天然类胡萝卜素一般是用正己 烷、 正丁垸等直链垸烃， 二氯甲垸、 氯仿、 或乙酸乙酯、 乙酸异丁酯 等酯类提取的， 这些溶剂往往是非极性或极性较弱， 但在溶解萃取过 程中往往会将少量的脂溶性纤维素也被提取出来，所以在后续过程中 尽量用极性较强的有机溶剂去除这些脂溶性纤维素。
在本发明中， 选择对类胡萝卜素溶解性很好而对纤维素溶解性差 的强极性有机溶剂四氢呋喃来去除类胡萝卜素晶体中的脂溶性纤维 素。
其次， 根据磷脂的理化性质中其不溶于丙酮或丁酮而类胡萝卜素 在丙酮或丁酮中可溶的特点， 将类胡萝卜素溶解于丙酮或丁酮中， 通 过过滤去除类胡萝卜素晶体中存在的少量的磷脂。
最后， 将去除脂溶性纤维和磷脂的类胡萝卜素晶体通过一定的微 粉碎措施变成微粉， 将此微粉与植物油混合就可得到高含量、流动性 好的类胡萝卜素油悬浮液， 方便随后的在食品或药物生产上的添加。
根据本发明， 步骤 （1 ) 中四氢呋喃的体积用量 （ml ) 与类胡萝 卜素晶体的最初投料重量 （g) 的比例为 5〜25： l o ; 类胡萝卜素晶体 与四氢呋喃混合， 搅拌升温至回流温度 50~70°C溶解， 该溶解时间为 0.5〜2.0hr。
根据本发明， 步骤 （2 ) 中酮类溶剂的体积用量 （ml ) 与类胡萝 卜素晶体的最初投料重量 （g) 的比例为 20〜80: 1， 所述酮类溶剂为 丙酮或丁酮；浓缩物与酮类溶剂混合，升温至回流温度 60~80 C溶解， 该溶解时间为 0.5〜2.0hr。将母液中酮类溶剂浓缩至干，加入无水乙醇 的体积用量 （ml ) 为类胡萝卜素晶体的最初投料重量 （g) 的比例为 0.1-5： l o
根据本发明， 步骤 （3 ) 中所述植物油为葵花籽油、 菜籽油、 玉 米油、 花生油、 大豆油、 芝麻油、 棉籽油、 红花油、 油茶籽油、 和 橄榄油中的一种或多种； 类胡萝卜素晶体的研磨方式为超微粉碎、 球磨粉碎、 或气流粉碎。
根据本发明，所得到所述类胡萝卜素油悬浮液中类胡萝卜素含量 在 10.0~45.0wt.%时， 所述类胡萝卜素油悬浮液在 5〜25 °C时就具有良 好的流动性能， 同时在应用时不需额外的加热步骤。
根据本发明， 所述类胡萝卜素晶体为 beta-胡萝卜素晶体、 虾青 素晶体、 斑蝥黄素晶体、 叶黄素晶体、 玉米黄质晶体、 或番茄红素晶 体。所述类胡萝卜素晶体或从全化学合成得到， 或从植物原料中提取 得到， 或通过发酵法制备得到。 步骤 （1 ) 中所述类胡萝卜素晶体的 UV含量为 50.0%〜100.0 wt.%，磷含量为 0.1%~4.5 wt.%,灼烧残渣为 0.01%~3.0 wt.%。 步骤 （2 ) 中所述类胡萝卜素晶体的 UV 含量为 56.1~99.8wt.%, 磷含量为 0.01〜1.0 wt.%， 灼烧残渣为 0.01~1.0 wt.%。
根据本发明的另一方面，本发明还提供了一种所述低粘度高流动 性类胡萝卜素油悬浮液在制备食品、 膳食补充剂及药品中的应用。
下面具体地描述本发明方法的具体制备过程为： 将类胡萝卜素与 5-25 倍四氢呋喃混合后搅拌升温至回流温度 （50〜70°C左右）， 保温 0.5〜2.0hr,过滤，能除去少量脂溶性纤维，将母液中四氢呋喃浓缩至千。 在浓縮物中重新投入 20~80倍量的酮类溶剂如丙酮、丁酮中， 升温至 回流温度溶解， 保温 0.5〜2.0hr， 过滤去除大部分磷脂， 将母液中有机 溶剂浓缩至干，加入投料量 0.1~5倍量的无水乙醇，室温下搅拌结晶， 过滤， 最后通过真空干燥即可得类胡萝卜素晶体， 晶体中类胡萝卜素 含量比处理前能提高 2〜8个百分点。 '
将得到的高含量的类胡萝卜素晶体通过适当的方式如超微粉碎、 球磨、气流粉碎进行粉碎， 再与适量的油混合均匀， 就可得到所需含 量的油悬浮液， 相同含量时， 油悬浮液的粘度比未处理晶体对应的油 悬浮液的粘度小得多， 前者的流动性较好， 这样在灌装软胶囊时就具 有良好的可操作性， 不需要额外的加热溶解过程， 避免了可能的由于 温度升高造成的含量下降， 且单个胶囊之间有效成分的含量均一。 具体实施方式 「
以下将结合实施例对本发明做进一步说明，本发明的实施例仅用 于说明本发明的技术方案， 并非限定本发明。 实施例 1
取从万寿菊花中提取得到的 500 g 叶黄素晶体 （UV 含量： 85.4wt.%, 磷含量： 2.56 wt.%， 灼烧残渣： 1.7 wt.%)， 加入四氢呋喃 5000 ml, 升温至 65°C， 搅拌溶解 0.5 hr后， 过滤， 滤饼为黑褐色粘 稠状物质， 烘干后重量为 7.53 g。
将上述母液中的四氢呋喃浓缩至干， 加入 10.0 L丙酮， 再升温至 60°C下回流 0.5 hr, 过滤得磷脂膏状物约 14.3 g， 将母液浓缩至干， 加入无水乙醇 200 ml后过滤得精制过的叶黄素晶体， 晶体烘干后重 量为 416 g o晶体中叶黄素 UV含量为 91.3 wt.%,磷含量为 0.05 wt.%, 灼烧残渣 0.03 wt.%。
称取精制后的叶黄素晶体 250g 与 350g 葵花籽油在球磨机中研 磨， 再补葵花籽油 40g， 得叶黄素的油悬浮液， 其中叶黄素含量为 35.7wt.%, 此油悬浮液具有良好的流动性能，在 5°C时可以自由流动。 实施例 2
取由发酵法生产得到的 300 g 天然番茄红素晶体 （UV 含量： 50.0wt.%, 磷含量： 3.17 wt.%, 灼烧残渣： 3.0 wt.%), 加入四氢呋喃 4500 ml, 升温至 50°C， 搅拌溶解 2.0 hr后， 过滤， 滤饼为黑褐色粘 稠状物质， 烘干后重量为 6.47 g。
将上述母液中的四氢呋喃浓缩至干， 加入 12.0 L丙酮， 再升温至 60Ό下回流 0.5 hr, 过滤得磷脂膏状物约 12.4 g， 将母液浓缩至干， 加入无水乙醇 30 ml后过滤得精制过的天然番茄红素晶体， 晶体烘干 后重量为 253.0 go 晶体中番茄红素 UV含量为 56.1 wt.%, 磷含量为 0.5 wt.%, 灼烧残渣 0.02 wt.%。
称取精制后的天然番茄红素晶体 210 g经气流粉碎后与 968 g玉 米油混合搅拌约 l.Ohr得番茄红素的油悬浮液， 其中番茄红素含量为 10.0 wt.%, 此油悬浮液具有良好的流动性能， 在 10°C时可以自由流 动。 实施例 3
取从棕榈油中提纯得到的 450 g天然 beta-胡萝卜素晶体 （UV含 量： 86.7 wt.%， 磷含量： 4.5 wt.%， 灼烧残渣： 1.6 wt.%)， 加入四氢 呋喃 2250 ml, 升温至 70°C， 保压搅拌溶解 0.5 hr后， 过滤， 滤饼为 黑褐色粘稠状物质， 烘干后重量为 8.24 g。
将上述母液中的四氢呋喃浓縮至干， 加入 9.0 L丁酮， 再升温至 80°C下回流 2.0 hr， 过滤得磷脂膏状物约 24.6 g， 将母液浓缩至干， 加入无水乙醇 180 ml后过滤得精制过的天然番茄红素晶体， 晶体烘 干后重量为 401.0g。 晶体中 beta-胡萝卜素 UV含量为 91.5 wt.%, 磷 含量为 1.0 wt.%， 灼烧残渣 0.5 wt.%。
称取精制后的 beta-胡萝卜素晶体 210 g与 300 g花生油在球磨机 中混合研磨约 1.5hr后补充 120 g花生油搅拌均匀即得 beta-胡萝卜素 的油悬浮液， 其中 beta-胡萝卜素含量为 30.5 wt.%， 此油悬浮液具有 良好的流动性能， 在 25°C时可以自由流动。
取 100 g玉米黄质晶体（以天然的叶黄素为原料， 通过转位得到） (UV含量： 90.5 wt.%， 磷含量： L54 wt.%， 灼烧残渣： 2.7 wt.%)， 加入四氢呋喃 1500 ml， 升温至 60°C， 搅拌溶解 l .O hr后， 过滤， 滤 饼为黑褐色粘稠状物质， 烘干后重量为 3.12 g。
将上述母液中的四氢呋喃浓缩至干， 加入 8.0 L丙酮， 再升温至 60°C下回流 L5 hr， 过滤得磷脂膏状物约 2.41 g， 将母液浓缩至千， 加入无水乙醇 500 ml后过滤得精制过的玉米黄质晶体， 晶体烘干后 重量为 87.0 g。 晶体中玉米黄质 UV含量为 95.8 wt.%， 磷含量为 0.01 wt.%, 灼烧残渣 1.0 wt.%。
称取精制后的玉米黄质晶体 75 g与 150 g菜籽油在球磨机中混合 研磨约 1.5hr后补充 55 g花生油搅拌均匀即得玉米黄质的油悬浮液， 其中玉米黄质含量为 25.7wt.%，此油悬浮液具有良好的流动性能， 在 5°C时可以自由流动。 取由发酵法生产得到的 400 g虾青素晶体 （UV含量： 96.4 wt.%， 磷含量： 1.87 wt.%, 灼烧残渣： 1.8 wt.%), 加入四氢呋喃 10 L， 升 温至 5(TC， 搅拌溶解 0.5 hr后， 过滤， 滤饼为黑褐色粘稠状物质， 烘 干后重量为 8.51 g。 ―
将上述母液中的四氢呋喃浓縮至干， 加入 15.0 L丁酮， 再升温至 80°C下回流 1.0 hr， 过滤得磷脂膏状物约 10.2 g， 将母液浓缩至干， 加入无水乙醇 100 ml后过滤得精制过的天然虾青素晶体， 晶体烘干 后重量为 359.0g。晶体中虾青素 UV含量为 99.2 wt.%,磷含量为 0.01 wt.%, 灼烧残渣 0.08 wt.%。
称取精制后的虾青素晶体 300 g经超微粉碎后与 620 g玉米油与 葵花籽的混合油 (2: 1)搅拌约 l .Ohr得虾青素的油悬浮液， 其中虾青素 含量为 32.6 wt.%， 此油悬浮液具有良好的流动性能， 在 10°C时可以 自由流动。 实施例 6
取 550 g全化学合成的斑蝥黄素晶体 （UV含量： 100.0 wt.%， 磷 含量： 0.1 wt.% ， 灼烧残渣： 0.01 wt.%， 加入四氢呋喃 13.75 L， 升 温至 50°C， 搅拌溶解 l.O hr后， 过滤，.滤饼为黑褐色粘稠状物质， 烘 干后重量为 2.51 g。
将上述母液中的四氢呋喃浓缩至干， 加入 20.0 L丁酮， 再升温至 80°C下回流 l.O hr, 过滤得磷脂膏状物约 4.2 g， 将母液浓縮至干， 加 入无水乙醇 300 ml后过滤得精制过的斑蝥黄素晶体， 晶体烘干后重 量为 539.0g。 晶体中斑蝥黄 UV 含量为 99.8 wt.% , 磷含量为 0.06wt.% ， 灼烧残渣 0.01 wt.% 。
称取精制后的斑蝥黄素晶体 200 g经超微粉碎后与 244 g红花油 与芝麻油的混合油 (1 : 1)搅拌约 LOhr得斑蝥黄素的油悬浮液， 其中斑 蝥黄素含量为 45.0 wt.%， 此油悬浮液具有良好的流动性能， 在 15 °C 时可以自由流动。 实施例 7 (比较实施例 1 )
取 150 g实施例 4中的玉米黄质晶体与 410 g菜籽油在球磨机中 混合研磨约 1.5hr后混合物在 25°C时根本没有流动性， 此时混合物中 玉米黄质含量为 24.2 wt.%。 继续补充菜籽油， 直至再补足 384.0 g， 混合物在 25°C才开始具有良好的流动性能， 此油悬浮液中玉米黄质 的含量为 14.3 wt.%。 实施例 8 (比较实施例 2)
取 100 g实施例 4中玉米黄质晶体未经四氢呋喃处理而直接加入 8.0 L丙酮， 升温至 60°C下回流 1.5 hr， 过滤得磷脂膏状物约 3.27 g， 将母液浓缩至干， 加入无水乙醇 50 ml后过滤得精制过的玉米黄质晶 体，晶体烘干后重量为 91.0 g o晶体中玉米黄质紫外含量为 93.6 wt.%, 磷含量为 0.01 wt.%, 灼烧残渣 1.8 wt. 。
称取精制后的玉米黄质晶体 75 g与 150 g菜籽油在球磨机中混合 研磨约 1.5hr后补充 55 g花生油搅拌均匀即得玉米黄质的油悬浮液， 其中玉米黄质含量为 25.7 wt.%, 此油悬浮液加热到 40Ό时仍无流动 性，在搅拌情况下继续补加菜籽油 114 g时油悬浮液在 25 °C才开始有 流动性， 此油悬浮液中玉米黄质的含量为 17.8 wt.%。
由上述实施例 1~6和采用现有技术的实施例 7和 8可以得到表 1 的对比结果：
类胡萝卜素油悬浮液的流动性能
Figure imgf000014_0001
从采用现有技术 1的实施例 7 (比较实施例 1 ) 与采用本发明的 实施例 4的对比可以看出，通过本发明揭示的方法对玉米黄质晶体进 行前处理后， 在保证良好流动性的前提下， 本发明的油悬浮液含量可 以由 14.3 wt.% (现有技术） 提高到 25.7 wt.% (本发明） 时， 现有技 术在 25°C时才有流动性， 而本发明在 5°C时就有比较好的流动性能。 从采用现有技术 2的实施例 8 (比较实施例 2 ) 与采用本发明的 实施例 4的对比可以看出，通过本专利揭示的方法对玉米黄质晶体进 行前处理后， 在保证良好流动性的前提下， 其油悬浮液含量可以由 17.8 wt.% (现有技术） 提高到 25.7 wt.% (本发明） 时， 现有技术 在 25°C时才有流动性， 而本发明在 5°C时就有比较好的流动性能。
本发明通过上面的实施例进行举例说明， 但是， 应当理解， 本发 明并不限于这里所描述的特殊实例和实施方案。在这里包含这些特殊 实例和实施方案的目的在于帮助本领域中的技术人员实践本发明。任 何本领域中的技术人员很容易在不脱离本发明精神和范围的情况下 进行进一步的改进和完善，因此本发明只受到本发明权利要求的内容 和范围的限制，其意图涵盖所有包括在由所附权利要求所限定的本发 明精神和范围内的备选方案和等同方案。

Claims

权 利 要 求 书
1、 一种制备低粘度高流动性类胡萝卜素油悬浮液的方法， 所述 方法包括如下步骤：
( 1 ) 将类胡萝卜素晶体与四氢呋喃混合， 搅拌升温至回流温度 50〜70°C溶解， 过滤去除脂溶性纤维素， 将母液中四氢呋喃浓缩至干， 得到浓缩物；
( 2) 将浓缩物与酮类溶剂混合， 升温至回流温度 60~80°C溶解， 过滤去除不溶性磷脂， 将母液中酮类溶剂浓缩至干， 加入无水乙醇在 室温下搅拌结晶、 过滤， 通过真空干燥得到类胡萝卜素晶体；
( 3 ) 将类胡萝卜素晶体充分研磨后与植物油混合、 或类胡萝卜 素晶体与植物油混合研磨后再补充植物油，得到低粘度高流动性类胡 萝卜素油悬浮液。
2、 如权利要求 1所述的方法， 其中， 步骤 （1 ) 中四氢呋喃的体 积用量与类胡萝卜素晶体的最初投料重量的比例为 5〜25： 1。
3、 如权利要求 1 所述的方法， 其中， 步骤 （1 ) 中溶解时间为 0.5〜2.0hr。
4、 如权利要求 1所述的方法， 其中， 步骤 （2 ) 中酮类溶剂的体 积用量与类胡萝卜素晶体的最初投料重量的比例为 20〜80: 1。
5、 如权利要求 1 所述的方法， 其中， 步骤 （2 ) 中溶解时间为 0.5~2.0hr。
6、 如权利要求 1或 4所述的方法， 其中， 步骤 （2 ) 中所述酮类 溶剂为丙酮或丁酮。
7、 如权利要求 1所述的方法， 其中， 步骤 （2 ) 中所述无水乙醇 的体积用量为类胡萝卜素晶体的最初投料重量的比例为 0.1〜5： 1。
8、 如权利要求 1所述的方法， 其中， 步骤 （3 ) 中所述植物油为 葵花籽油、 菜籽油、 玉米油、 花生油、 大豆油、 芝麻油、 棉籽油、 红 花油、 油茶籽油、 和橄榄油中的一种或多种。
9、 如权利要求 1所述的方法， 其中， 步骤 （3 ) 中类胡萝卜素晶 体的研磨方式为超微粉碎、 球磨粉碎、 或气流粉碎。
10、 如权利要求 1所述的方法， 其中， 所述类胡萝卜素油悬浮液 中类胡萝卜素含量在 10.0〜45.0wt.%时， 所述类胡萝卜素油悬浮液在 5〜25°C时就具有良好的流动性能， 同时在应用时不需额外的加热步 骤。
11、 如权利要求 1 所述的方法， '其中， 所述类胡萝卜素晶体为 beta-胡萝卜素晶体、 虾青素晶体、 斑蝥黄素晶体、 叶黄素晶体、 玉米 黄质晶体、 或番茄红素晶体。
12、 如权利要求 1、 2、 4、 7或 11所述的方法， 其中， 所述类胡 萝卜素晶体或从全化学合成得到， 或从植物原料中提取得到， 或通过 发酵法制备得到。
13、 如权利要求 12所述的方法， 其中， 步骤（1 ) 中所述类胡萝 卜素晶体的 UV含量为 50.0〜100.0wt.%， 磷含量为 0.1〜4.5wt.%, 灼 烧残渣为 0.01〜3.0wt.%。
14、 如权利要求 12所述的方法， 其中， 步骤（2 ) 中所述类胡萝 卜素晶体的 UV含量为 56.1〜99.8wt.%， 磷含量为 0.01〜1.0 wt.%, 灼 烧残渣为 0.01〜1.0 wt.%。
15、 一种如权利要求 1~14任一所述的低粘度高流动性类胡萝卜 素油悬浮液在制备食品、 膳食补充剂及药品中的应用。
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