WO2020221052A1 - 一种α-生育酚的微球及其制备方法 - Google Patents

一种α-生育酚的微球及其制备方法 Download PDF

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WO2020221052A1
WO2020221052A1 PCT/CN2020/085744 CN2020085744W WO2020221052A1 WO 2020221052 A1 WO2020221052 A1 WO 2020221052A1 CN 2020085744 W CN2020085744 W CN 2020085744W WO 2020221052 A1 WO2020221052 A1 WO 2020221052A1
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tocopherol
microspheres
betaine
preparation
animal
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French (fr)
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梅雪锋
朱冰清
张奇
陆鹂烨
王建荣
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中国科学院上海药物研究所
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/105—Aliphatic or alicyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/174—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating
    • 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
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/045—Organic compounds containing nitrogen as heteroatom
    • 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
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • 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 a microsphere of alpha-tocopherol and a preparation method thereof.
  • Vitamin E is an important fat-soluble vitamin with a wide range of physiological functions in animals/humans. As an effective antioxidant and immunomodulator, it plays an important role in enhancing animal immunity, antioxidant capacity, preventing infertility, improving animal production performance, and improving animal meat quality. Therefore, it is widely used in food processing, animal feed and human nutrition and health products.
  • Vitamin E includes natural vitamin E and synthetic vitamin E.
  • Synthetic vitamin E is dl- ⁇ -tocopherol.
  • Natural tocopherol includes ⁇ , ⁇ , ⁇ , ⁇ -tocopherol and ⁇ , ⁇ , ⁇ , ⁇ -tocopherol.
  • Tocopherol itself is in the form of oily liquid, sensitive to oxygen, and unstable when exposed to the air. Therefore, it is generally derivatized into tocopherol acetate to protect the phenolic hydroxyl group from oxidation; further, in order to improve the use of vitamin E products Convenience, to expand its application range, needs to be made into corresponding solid preparations. At present, there are mainly the following two technical methods: (1) Microcapsule technology.
  • Vitamin E products obtained by microencapsulation technology usually have good water solubility and are used in the food and pharmaceutical fields.
  • the microencapsulation technology mostly uses spray drying technology, which has poor control over the particle size, and the product particle shape and size are not uniform.
  • Silica adsorption technology Considering economic benefits, the feed industry mostly uses silica-adsorbed vitamin E products. Although the production cost is reduced, the presence of silica is an obstacle to the release and absorption of vitamin E.
  • the vitamin E powder prepared by adsorption technology or microcapsule technology has excellent fluidity, which helps vitamin E and other feed additives or food raw materials to be uniformly mixed.
  • due to the limited adsorption/embedding capacity of silica or high molecular polymers to tocopherol acetate the maximum loading of tocopherol acetate in commercially available vitamin E powder is only 50%;
  • Patent CN105061459A discloses a spherical crystal of clopidogrel hydrogen sulfate I crystal form.
  • the spherical crystal has significant advantages in terms of solvent residue, bulk density and fluidity, which is beneficial to the realization of the powder direct compression preparation process;
  • patent CN108567744A passed Alkali-dissolved acid precipitation method and spherical agglomeration method prepare a kind of spherical particles of hydrochlorothiazide.
  • the particles significantly increase the dissolution rate of hydrochlorothiazide and at the same time improve its powder properties, and are suitable for direct compression.
  • these spherical crystallization techniques are all aimed at a single solid component, and there is no report on the spherical crystallization of oily substances.
  • the patent CN107875139A uses microfluidic technology to prepare a core-shell structure of ⁇ -tocopherol/calcium alginate gel microspheres, although the obtained microspheres have good sphericity, uniform particle size and low core material content.
  • this technical solution requires the use of more wall materials, including sodium alginate, Tween 80, and nano-calcium carbonate.
  • Vitamin E is an important nutrient fortifier and feed additive. Its powder properties determine its convenience and application range, and the level of bioavailability is an important factor affecting its biological functions. There are many factors affecting the bioavailability of a compound, including its solubility, dissolution rate, permeability, enzyme activity in the body, and transporters.
  • the absorption of ⁇ -tocopherol acetate in the human body involves a series of physical, chemical and biological processes. ⁇ -tocopherol acetate is first released from its preparation and hydrolyzed to free ⁇ -tocopherol under the action of digestive enzymes.
  • Alpha-tocopherol needs to be combined with other lipid substances (such as phospholipids, fatty acids, glycerides, etc.) under the action of bile salts to form mixed particles, which are absorbed by epithelial cells.
  • the complex absorption process can be regulated by a variety of factors, making the decrease or increase of vitamin E bioavailability often unobvious or even unpredictable. Studies have shown that when given silica-adsorbed vitamin E powder, part of the tocopherol acetate is still adsorbed in the silica matrix, and cannot be effectively emulsified with bile into mixed micelles, which hinders its hydrolysis and Further absorption (Mol. Nutr. Food Res. 2013).
  • Betaine is a quaternary amine-type water-soluble alkaloid with three active methyl groups. It is a good donor of the body's methyl groups. It is widely used in feed due to its wide source and rich biological functions.
  • Patent CN102258124A discloses a composite betaine, which contains anhydrous betaine, vitamin B12, sodium chloride, potassium chloride, sodium bicarbonate and glucose. The provided composite betaine can replace methionine with betaine and significantly improve the animal Mineral metabolism in the body.
  • Chang Wenhuan et al. found that adding betaine to feed can significantly increase the content of muscle fat and flavor amino acids in muscle, improve the composition of fatty acids in muscle, and thereby improve the flavor quality of chicken.
  • the ⁇ -tocopherol microspheres provided by the present invention can be used to prepare animal feed or human nutrition and health products.
  • the present invention uses small molecule betaine as a carrier, and can prepare ⁇ -tocopherol microspheres by cooling and crystallization.
  • the spherical particles have high ⁇ -tocopherol content, good sphericity and fluidity, high melting point, and chemical Good stability; more importantly, the microspheres can significantly increase the blood concentration of ⁇ -tocopherol at the same dose.
  • the present invention provides a microsphere of ⁇ -tocopherol, which contains ⁇ -tocopherol and betaine, wherein the mass fraction of ⁇ -tocopherol is 50%-90%; the mass fraction of betaine is 10% -50%.
  • the particle size distribution of the microspheres of the ⁇ -tocopherol is 10-500 microns; more preferably, the particle size distribution is 50-200 microns.
  • the ⁇ -tocopherol is selected from natural ⁇ -tocopherol (d- ⁇ -tocopherol) and synthetic tocopherol (dl- ⁇ -tocopherol).
  • the d- ⁇ -tocopherol microspheres are characterized in that: the X-ray powder diffraction expressed in 2 ⁇ angles has diffraction angles of 3.8 ⁇ 0.2, 5.7 ⁇ 0.2, 7.6 ⁇ 0.2, 9.6 ⁇ 0.2, 11.5 ⁇ 0.2, 13.5 ⁇ 0.2, 16.4 ⁇ 0.2, 17.4 ⁇ 0.2, 21.3 ⁇ 0.2 degrees have characteristic peaks; preferably, there are characteristic peaks at 15.3 ⁇ 0.2, 16.4 ⁇ 0.2, 19.5 ⁇ 0.2 degrees; more preferably , Which has the X-ray powder diffraction pattern shown in Figure 1.
  • the d- ⁇ -tocopherol microspheres are characterized in that: measured by differential scanning calorimetry, they have an endothermic peak at 44 ⁇ 2°C, and the melting start temperature of the microspheres is 106 ⁇ 2 °C, the maximum peak value is 107 °C; preferably, it has the differential scanning calorimetry chart shown in FIG. 2.
  • the d- ⁇ - tocopherol microspheres characterized in that: by using infrared Fourier transform infrared spectrometer to obtain the absorption spectrum qualitatively using the following important qualitative said wave number: 3341cm -1, 2928cm - 1 , 2866cm -1 , 1651cm -1 , 1464cm -1 , 1416cm -1 , 1386cm -1 , 1336cm -1 , 1264cm -1 , 1228cm -1 , 1170cm -1 , 1094cm -1 , 930cm -1 , 892cm -1 , 728 cm -1 , 641 cm -1 ; preferably, have the infrared spectrum shown in FIG. 3.
  • the d- ⁇ -tocopherol microspheres are characterized in that the Raman spectroscopy obtained by using a laser Raman spectrometer is qualitatively characterized by the following important wavenumbers: 2923 cm -1 , 2869 cm -1 , 1579 cm -1 , 1456 cm -1 , 1335 cm -1 , 783 cm -1 , 589 cm -1 , 485 cm -1 ; preferably, it has the Raman spectrum shown in FIG. 4.
  • the ⁇ -tocopherol microspheres of the present invention can be obtained by the following preparation method: dissolving ⁇ -tocopherol and betaine in an organic solvent, stirring and dissolving, and cooling to -30°C-0°C to precipitate a white precipitate, Centrifuge and dry the precipitate to obtain ⁇ -tocopherol microsphere particles.
  • the purity of the ⁇ -tocopherol used is greater than or equal to 90%;
  • the purity of the ⁇ -tocopherol used is greater than or equal to 95%
  • the organic solvent used is methanol or ethanol
  • the temperature for stirring and dissolving is 20°C-50°C;
  • the cooling rate is 0.1°C-4°C/min
  • the mass ratio of the ⁇ -tocopherol to the betaine is 0.5:1-9:1;
  • the mass volume ratio of the d- ⁇ -tocopherol to the organic solvent is less than or equal to 200 g/L; when the ⁇ -tocopherol is dl- In the case of ⁇ -tocopherol, the mass-volume ratio of the dl- ⁇ -tocopherol to the organic solvent is less than or equal to 250 g/L;
  • the precipitation is performed under stirring or vortexing conditions.
  • the invention also provides the use of the ⁇ -tocopherol microspheres in the preparation of animal feed or human nutritional health products.
  • the animal feed can be used to increase the concentration of ⁇ -tocopherol in the plasma or tissues of the animal, thereby enhancing the immunity of the animal and improving the animal’s reproduction. Litter size and vitality of animal pups, improve the quality of animal meat.
  • the human nutrition and health products can be used to increase the concentration of ⁇ -tocopherol in human plasma or tissues, thereby enhancing the physiological functions related to tocopherol , Such as improving anti-oxidation, improving human immunity, whitening, lightening, anti-aging, and use in the process of fertility.
  • the preparation method of ⁇ -tocopherol microspheres provided by the present invention is simple, the carrier composition used is single (only betaine), the cost is low, and it is easy for industrial scale-up;
  • the ⁇ -tocopherol microspheres provided by the present invention have a content of ⁇ -tocopherol as high as 50%-90%;
  • ⁇ -tocopherol microspheres have complete sphericity, good fluidity and uniform particle size
  • the ⁇ -tocopherol microspheres of the present invention have excellent chemical stability and higher bioavailability.
  • the concentration of ⁇ -tocopherol in plasma when the dl- ⁇ -tocopherol microspheres of the present invention are fed to rats Significantly increased.
  • the concentration of ⁇ -tocopherol in plasma also significantly improved.
  • the increase in the concentration of ⁇ -tocopherol is an important condition for its biological activity. Therefore, the ⁇ -tocopherol microspheres of the present invention can be used to increase the concentration of ⁇ -tocopherol in the plasma or tissues of animals or humans, thereby improving the biological functions related to vitamin E. In order to achieve this goal of the invention, the microspheres can be used in the preparation of animal feed and human nutrition and health products.
  • animals include mammals and non-mammals.
  • mammals include ruminants and non-ruminant animals, such as pigs, cattle, horses, sheep, and pet animals such as dogs and cats;
  • preferred examples of non-mammals are poultry and aquatic animals, such as chickens, ducks, and fish. And shrimp etc.
  • Figure 1 is an X-ray powder diffraction (XRPD) pattern of d- ⁇ -tocopherol microspheres provided in Example 1;
  • Example 2 is a differential scanning calorimetry (DSC) chart of d- ⁇ -tocopherol microspheres provided in Example 1;
  • Figure 3 is an infrared spectrum (IR) chart of the d- ⁇ -tocopherol microspheres provided in Example 1;
  • Example 4 is a Raman spectrum (Raman) diagram of d- ⁇ -tocopherol microspheres provided in Example 1;
  • Figure 5 is a scanning electron micrograph of d- ⁇ -tocopherol microspheres obtained in Example 1;
  • Figure 6 is a scanning electron micrograph of d- ⁇ -tocopherol microspheres obtained in Example 2.
  • Figure 7 is a scanning electron micrograph of the dl- ⁇ -tocopherol microspheres obtained in Example 3.
  • Example 8 is a scanning electron micrograph of dl- ⁇ -tocopherol microspheres obtained in Example 4.
  • Example 9 is a scanning electron micrograph of the d- ⁇ -tocopherol non-microspheres obtained in Example 5.
  • Example 2 The d- ⁇ -tocopherol microspheres and d- ⁇ -tocopherol prepared in Example 1 were compared in the stability test under accelerated conditions. The conditions were: 40°C/75% relative humidity. The results are shown in Table 1-2. Show.
  • Table 1 shows the content change of d- ⁇ -tocopherol oil itself under accelerated test conditions (40°C/75% relative humidity);
  • Table 2 shows the content change of d- ⁇ -tocopherol microspheres obtained in Example 1 under accelerated test conditions (40°C/75% relative humidity);
  • the content was determined by HPLC, and the calculation method of the content was external standard method.
  • the initial content of ⁇ -tocopherol in d- ⁇ -tocopherol oil was 96.6%. Under accelerated test conditions (40°C/75% relative humidity), the content of ⁇ -tocopherol decreased to 93.6% after 6 months.
  • the initial content of ⁇ -tocopherol in d- ⁇ -tocopherol microspheres was 86.4%. After 6 months, the content of ⁇ -tocopherol was still as high as 86.5%. It can be seen that the content of ⁇ -tocopherol in the d- ⁇ -tocopherol microspheres is basically unchanged, showing excellent chemical stability.
  • Example 7 Comparison of plasma concentration of dl- ⁇ -tocopherol microspheres and silica-adsorbed dl- ⁇ -tocopherol acetate powder in rats, dose: 80mg/kg
  • dl- ⁇ -tocopherol microspheres prepared in Example 3, in which the content of dl- ⁇ -tocopherol is 87.5%; commercially available silica-adsorbed dl- ⁇ -tocopherol acetate powder, purchased From Zhejiang Xinhecheng Co., Ltd., the content of dl- ⁇ -tocopherol acetate is 51.1%; AIN-G93 feed without vitamin E was purchased from Fanbo Biotechnology Co., Ltd.
  • Sample preparation Suspend the above-mentioned dl- ⁇ -tocopherol microspheres and dl- ⁇ -tocopherol acetate powder adsorbed by silicon dioxide in 0.5% sodium carboxymethyl cellulose + 0.5% sodium lauryl sulfate, respectively In aqueous solution.
  • the experimental plan is as follows:
  • Dosage converted into 80mg/kg dl- ⁇ -tocopherol
  • Administration form intragastric administration in the form of suspension
  • Time point of blood collection 0, 1, 2, 3, 4, 6, 8, 10, 24 hours (blood collection method is blood collection from the orbital venous plexus)
  • Plasma treatment method 100 ⁇ L plasma sample+200 ⁇ L ethanol (1%wt/vol ascorbic acid)+1mL n-hexane, vortex for 1min, centrifugation (5min, 10000rpm); take 0.8mL n-hexane solution, dry with N 2 and re-use 200 ⁇ L ethanol Reconstitute, vortex for 1 min, HPLC test.
  • the maximum blood concentration of dl- ⁇ -tocopherol microspheres prepared by the present invention can reach 12.9 ⁇ g/mL, while feeding commercially available silica-adsorbed dl- ⁇ -tocopherol acetate
  • the maximum blood concentration of dl- ⁇ -tocopherol acetate powder adsorbed by powder silica is only 8.3 ⁇ g/mL.
  • the use of the dl- ⁇ -tocopherol microspheres of the present invention can significantly increase the concentration of tocopherol in the plasma compared to commercially available dl- ⁇ -silica adsorption powder adsorbed by silica.
  • Example 8 Comparison of plasma concentration of d- ⁇ -tocopherol microspheres and d- ⁇ -tocopherol acetate powder in rats, dose: 80mg/kg
  • Experimental reagents the d- ⁇ -tocopherol microspheres prepared in Example 1, in which the content of d- ⁇ -tocopherol is 86.4%; commercially available food grade d- ⁇ -tocopherol acetate powder, purchased from Feng Yichunzhigu Biotechnology Co., Ltd., in which the content of d- ⁇ -tocopherol acetate is 50.5%; AIN-G93 feed without vitamin E, purchased from Fanbo Biotechnology Co., Ltd.
  • Sample preparation the above-mentioned d- ⁇ -tocopherol microspheres and d- ⁇ -tocopherol acetate powder were suspended in 0.5% sodium carboxymethyl cellulose + 0.5% sodium lauryl sulfate aqueous solution.
  • the experimental plan is as follows:
  • Dosage converted to 80mg/kg d- ⁇ -tocopherol
  • Administration form intragastric administration in the form of suspension
  • Time point of blood collection 0, 1, 2, 3, 4, 6, 8, 10, 24 hours (blood collection method is blood collection from the orbital venous plexus)
  • Plasma treatment method 100 ⁇ L plasma sample+200 ⁇ L ethanol (1%wt/vol ascorbic acid)+1mL n-hexane, vortex for 1min, centrifugation (5min, 10000rpm); take 0.8mL n-hexane solution, dry with N 2 and re-use 200 ⁇ L ethanol Reconstitute, vortex for 1 min, HPLC test.

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Abstract

一种α-生育酚的微球、其制备方法及用途。该微球以甜菜碱为载体，在搅拌或涡旋的作用下，通过冷却结晶的方法获得。所得微球的生育酚载量高，球形度和流动性好，熔点较高，并且具有优异的化学稳定性和更高的生物利用度，能够用于制备动物饲料或人类营养保健品。

Description

一种α-生育酚的微球及其制备方法 技术领域
本发明涉及一种α-生育酚的微球及其制备方法。
背景技术
维生素E是动物/人体内具有广泛生理功能的重要的脂溶性维生素。它作为一种有效的抗氧化剂和免疫调节剂，在增强畜禽免疫力、抗氧化能力及预防不孕症、提高畜禽生产性能和改善畜禽肉质等方面具有重要作用。因此，被广泛地应用于食品加工、动物饲料及人类营养保健品中。
维生素E包括天然维生素E和合成维生素E，合成维生素E即dl-α-生育酚，天然生育酚包括α，β，γ，δ-生育酚及α，β，γ，δ-三烯生育酚。生育酚本身为油状液体形态，对氧敏感，暴露在空气中不稳定，因此一般将其衍生化为生育酚醋酸酯，保护酚羟基使其不易被氧化；进一步地，为了提高维生素E产品的使用便利性，扩大其应用范围，需将其制成相应的固体制剂。目前主要有以下两种技术方法：(1)微胶囊技术。采用微胶囊技术得到的维生素E产品通常具有较好的水溶性，应用于食品和药品领域。但微胶囊技术多采用喷雾干燥技术，对颗粒尺寸的控制较差，产品颗粒形貌、大小不均一。(2)二氧化硅吸附技术。考虑到经济效益，饲料行业多采用二氧化硅吸附的维生素E产品，虽然降低了生产成本，但二氧化硅的存在对于维生素E的释放和吸收是一个障碍。吸附技术或微胶囊技术制备得到的维生素E粉末具有优异的流动性，有助于维生素E和其他饲料添加剂或食品原料均匀混合。但是，由于二氧化硅或高分子聚合物对生育酚醋酸酯的吸附/包埋能力有限，因此，市售的维生素E粉末中生育酚醋酸酯的最高载量仅为50％；。
将化合物制备形成规整的球形颗粒，能够使其获得良好的粉体学性质，如更好的过滤性能、流动性和压片性能。因此，球形结晶技术在医药生物和食品加工领域具有广泛的应用。专利CN105061459A公开了一种硫酸氢氯吡格雷I晶型的球形结晶，该球形结晶在溶剂残留、堆密度和流动性等方面具有显著的优势，有利于粉末直压制剂工艺的实现；专利CN108567744A通过 碱溶酸析法及球型聚集发制备得到了一种氢氯噻嗪的球形微粒，该微粒显著提高了氢氯噻嗪的溶出度，同时提高了其粉体学性质，适用于直接压片。但这些球形结晶技术均针对于单一的固体组分，对于油状物质的球形结晶还未有报道。对于维生素E，专利CN107875139A采用微流控技术制备得到了一种壳核结构的α-生育酚/海藻酸钙凝胶微球，虽然得到的微球球形度好、粒径均一且芯材含量可控，但是其该技术方案需使用到较多壁材，包括海藻酸钠、吐温80、纳米碳酸钙，此外，还需使用苯甲酸苄酯或白油作为稀释剂，因此，技术路线复杂、成本高，不利于工艺放大和商业使用；从上述已公开的文件中，尚未发现具有商业推广价值的α-生育酚微球颗粒。
维生素E作为重要的营养强化剂和饲料添加剂，粉体学性质决定了其使用便利性和应用范围，而生物利用度的高低则是影响其发挥相关生物学功能的重要因素。影响一个化合物生物利用度的因素是多方面的，包括其溶解度、溶出速率、渗透性、体内酶活性和转运体等。α-生育酚醋酸酯在人体内的吸收涉及一系列的物理化学和生物过程，α-生育酚醋酸酯首先从其制剂中释放，在消化酶的作用下水解为游离的α-生育酚。α-生育酚需要在胆盐的作用下与其它脂质物质(如磷脂质、脂肪酸、甘油酯等)结合成混合微粒，通过上皮细胞吸收。复杂的吸收过程可被多种因素调控，使得维生素E生物利用度的降低或提高往往是不显而易见的，甚至是无法预测的。研究表明，当给予二氧化硅吸附型的维生素E粉末时，部分生育酚醋酸酯仍然吸附在二氧化硅基质中，而无法有效地与胆汁乳化成混合微团，在一定程度上阻碍其水解和进一步吸收(Mol.Nutr.Food Res.2013)。
因此，提供一种载量高、流动性好、粒径均一、化学稳定并且生物利用度高的维生素E粉对于维生素E在食品加工、动物饲料及人类营养保健品中的应用具有重要意义。
甜菜碱是一种季胺型水溶性生物碱，具有三个活性甲基，是机体甲基的良好供体，以其广泛的来源和丰富的生物学功能，在饲料中被广泛应用。专利CN102258124A公开了一种复合甜菜碱，包含了无水甜菜碱、维生素B12、 氯化钠、氯化钾、碳酸氢钠和葡萄糖，所提供的复合甜菜碱可以使甜菜碱替代蛋氨酸，明显改善动物体内的矿物质代谢。常文环等人(动物营养学报，2015)研究发现饲料中添加甜菜碱可以显著提高肌肉中肌肉脂肪和风味氨基酸的含量，改善肌肉中脂肪酸的组成，从而改善鸡肉的风味品质。马文强等人(南京农业大学学报，2018)对母鼠妊娠期和哺乳期日粮添加甜菜碱对子代雌性大鼠机体铁代谢的影响及其机制进行了探究。虽然，已有较多文献研究了甜菜碱丰富的生物学功能，但是，在提高维生素E稳定性或生物利用度的研究中，尚未有相关报道。且上述文件均未教导或暗示甜菜碱能够促使维生素E在结晶过程中形成微球，并提高其化学稳定性和生物利用度。
已有较多文献报道提高动物血浆或组织中生育酚的浓度，将有利于生育酚在更大程度上发挥其生物学功能。如Leonel N Leal等人(J Sci Food Agric,2018)研究了喂食小羊不同剂量及来源的维生素E对屠宰后羊肉品质的影响，实验结果表明，维生素E能够减少油脂的氧化，保持羊肉的肉色及纹理，从而延长羊肉的保质期，剂量越高，效果越显著；并且，在相同剂量下，天然维生素E(RRR-α-生育酚醋酸酯)相比合成维生素E(all-rac-α-生育酚醋酸酯)表现出更优异的效果。Vicente
Figure PCTCN2020085744-appb-000001
(Meat Science,2005)和D.J.Buckley(Meat Science,1996)等人的研究也都得出了相似的结论。Anshan Shan等人(Poultry Science,2013)研究了维生素E(d-α-生育酚醋酸酯)对于产蛋鸡的产蛋量和蛋品质的影响，实验结果表明，维生素E提高了产蛋量、蛋黄比重，降低了蛋黄和蛋清中的胆固醇水平并提高了蛋黄和蛋清中的α-生育酚水平。Mohammed R.Larijani等人(African Journal of Fisheries Science)研究了不同维生素E(α-生育酚)剂量对斑马鱼的生长速度、存活率及繁殖率的影响，实验结果表明，摄取饲料中的维生素E含量越高，斑马鱼的体重增长越快，繁殖力越强。
因此，基于上述文献的研究结果，我们完全有依据认为，提高动物或人的血浆或组织中α-生育酚浓度将促使α-生育酚在更大程度上发挥其生物学功能，包括增强动物/人免疫力、抗氧化能力及预防不孕症、提高畜禽生产性能 和改善畜禽肉质等，因此，本发明提供的α-生育酚微球可以用于制备动物饲料或人类营养保健品。
发明内容
本发明利用小分子甜菜碱作为载体，通过冷却结晶的方法能够制备得到α-生育酚的微球，该球形颗粒中α-生育酚的含量高、球形度和流动性好、熔点较高、化学稳定性好；更重要的是，在相同剂量下，该微球能够显著提高α-生育酚的血药浓度。
本发明提供了一种α-生育酚的微球，该微球包含α-生育酚和甜菜碱，其中，α-生育酚的质量分数为50％-90％；甜菜碱的质量分数为10％-50％。
优选地，所述α-生育酚的微球粒径分布在10-500微米；更优选地，粒径分布为50-200微米。
优选地，所述α-生育酚，选自天然α-生育酚(d-α-生育酚)和合成生育酚(dl-α-生育酚)。
优选地，所述的d-α-生育酚的微球，其特征在于：以2θ角度表示的X-射线粉末衍射在衍射角为3.8±0.2，5.7±0.2，7.6±0.2，9.6±0.2，11.5±0.2，13.5±0.2，16.4±0.2，17.4±0.2，21.3±0.2度处具有特征峰；优选地，还在15.3±0.2，16.4±0.2，19.5±0.2度处具有特征峰；更优选地，其具有图1所示的X-射线粉末衍射图。
优选地，所述的d-α-生育酚的微球，其特征在于：通过差式扫描量热法测定，在44±2℃处具有吸热峰，微球熔化起始温度为106±2℃，最大峰值为107℃；优选地，其具有图2所示的差示扫描量热分析图。
优选地，所述的d-α-生育酚的微球，其特征在于：通过采用傅里叶变换红外光谱仪得到的红外吸收光谱定性，采用下面所述的重要波数定性：3341cm -1、2928cm -1、2866cm -1、1651cm -1、1464cm -1、1416cm -1、1386cm -1、1336cm -1、1264cm -1、1228cm -1、1170cm -1、1094cm -1、930cm -1、892cm -1、728cm -1、641cm -1；优选地，具有图3所示的红外光谱。
优选地，所述的d-α-生育酚的微球，其特征在于：通过采用激光拉曼光谱仪得到的拉曼光谱定性，采用下面所述的重要波数定性：2923cm -1、2869cm -1、1579cm -1、1456cm -1、1335cm -1、783cm -1、589cm -1、485cm -1；优选地，具有图4所示的拉曼光谱图。
本发明的α-生育酚的微球可通过以下制备方法获得：将α-生育酚和甜菜碱共同溶解于有机溶剂中，搅拌溶清，冷却至-30℃-0℃，析出白色沉淀物，离心，干燥沉淀物，得到α-生育酚的微球颗粒。
优选地，所用α-生育酚的纯度大于等于90％；
更优选地，所用α-生育酚的纯度大于等于95％；
优选地，所用有机溶剂为甲醇或乙醇；
优选地，所述搅拌溶清的温度为20℃-50℃；
优选地，所述冷却速度为0.1℃-4℃/分钟；
优选地，所述α-生育酚与所述甜菜碱的质量比为0.5:1～9:1；
优选地，当所述α-生育酚为d-α-生育酚时，所述d-α-生育酚与有机溶剂的质量体积比小于等于200g/L；当所述α-生育酚为dl-α-生育酚时，所述dl-α-生育酚与有机溶剂的质量体积比小于等于250g/L；
优选地，所述析出在搅拌或涡旋条件下进行。
本发明还提供了所述α-生育酚的微球在制备动物饲料或人类营养保健品中的用途。
当所述α-生育酚的微球用于制备动物饲料时，所述动物饲料可以用于提高动物的血浆或组织中的α-生育酚浓度，从而增强动物的免疫力、提高动物繁殖中的产仔数和动物幼仔的生命力、改善动物肉的品质。
当所述α-生育酚的微球用于制备人类营养保健品时，所述人类营养保健品可以用于提高人的血浆或组织中的α-生育酚浓度，从而增强涉及生育酚的生理功能，如提高抗氧化作用，提高人体免疫力、美白、淡斑、抗衰老以及在生育过程中的用途。
与现有技术相比，本发明的优点在于：
1)本发明提供的α-生育酚微球的制备方法简单，所用载体组成单一(仅为甜菜碱)，成本低廉，易于工业放大；
2)相比目前市售的二氧化硅吸附或微胶囊包埋的维生素E粉，本发明提供的α-生育酚微球，其中α-生育酚的含量高达50％-90％；
3)α-生育酚微球的球形度完整、流动性好、粒径均一；
4)申请人发现，出乎意料地，本发明的α-生育酚微球具有优异的化学稳定性和更高的生物利用度。相比市售的二氧化硅吸附的饲料级dl-α-生育酚醋酸酯粉，当对大鼠饲喂该本发明的dl-α-生育酚微球时，血浆中α-生育酚的浓度显著提高。相比市售的微胶囊包埋的食品级d-α-生育酚醋酸酯粉，当对大鼠饲喂该本发明的d-α-生育酚微球时，血浆中α-生育酚的浓度同样显著提高。α-生育酚浓度的增加是其发挥生物活性的重要条件。因此，本发明涉及的这种α-生育酚的微球可被应用于提高动物或人的血浆或组织中α-生育酚浓度，进而用以改善涉及维生素E相关的生物学功能。为了实现这一发明目标，该微球可被应用于制备动物饲料和人类营养保健品中。
在本发明的上下文中，动物包括哺乳动物和非哺乳动物。其中，哺乳动物的优选例子是反刍动物和非反刍动物，例如猪、牛、马、羊以及狗和猫的宠物动物等；非哺乳动物的优选例子是家禽和水产动物，例如鸡、鸭、鱼和虾等。
附图说明
图1是实施例1提供的d-α-生育酚微球的X-射线粉末衍射(XRPD)图；
图2是实施例1提供的d-α-生育酚微球的差示扫描量热分析(DSC)图；
图3是实施例1提供的d-α-生育酚微球的红外光谱(IR)图；
图4是实施例1提供的d-α-生育酚微球的拉曼光谱(Raman)图；
图5是实施例1得到的d-α-生育酚微球的扫描电镜照片；
图6是实施例2得到的d-α-生育酚微球的扫描电镜照片
图7是实施例3得到的dl-α-生育酚微球的扫描电镜照片；
图8是实施例4得到的dl-α-生育酚微球的扫描电镜照片。
图9是实施例5得到的d-α-生育酚非微球的扫描电镜照片。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。
实施例1(d-α-生育酚微球的制备)
将d-α-生育酚油(22g，纯度为98.7％)、甜菜碱粉末(11.5g)加入到甲醇(250mL)中，加热至25℃搅拌溶清，快速冷却，约10分钟后(2.7℃)析出大量白色沉淀物，进一步降温至-17℃，过滤，将得到的固体粉末干燥后，获得d-α-生育酚的微球粉末22.5g，收率为67.2％。
其XRPD图谱、DSC图、IR图、Raman图，扫描电镜照片分别见图1-5。
实施例2(d-α-生育酚微球的制备)
将d-α-生育酚油(22g，纯度为95.3％)、甜菜碱粉末(5.8g)加入到乙醇(250mL)中，加热至30℃搅拌溶清，快速冷却，约8分钟后(14℃)析出大量白色沉淀物，进一步降温至-12.5℃，过滤，将得到的固体粉末干燥后，获得d-α-生育酚的微球粉末20.9g，收率为75.2％。其扫描电镜照片如图6所示。
实施例3(dl-α-生育酚微球的制备)
将dl-α-生育酚(83g，纯度为91.4％)、甜菜碱(31.5g)加入到乙醇(500mL)中，加热至35℃搅拌溶清，快速冷却，约-12℃时析出大量白色沉淀物，进一步降温至-18℃，过滤，将得到的固体粉末干燥后，获得dl-α-生育酚的微球粉末76.7g，收率为70％。其扫描电镜照片如图7所示。
实施例4(dl-α-生育酚微球的制备)
将dl-α-生育酚(28.7g，纯度为92.7％)、甜菜碱(7.5g)加入到甲醇(125mL)中，加热至25℃搅拌溶清，快速冷却，约-12℃时析出大量白色沉淀物，进一步降温至-17℃，过滤，将得到的固体粉末干燥后，获得dl-α- 生育酚的微球粉末28.1g，收率为77.6％。其扫描电镜照片如图8所示。
实施例5(d-α-生育酚的非微球结晶)
将d-α-生育酚油(52.5g，纯度为98.7％)、甜菜碱粉末(14.1g)加入到甲醇(250mL)中，加热至40℃搅拌溶清，快速冷却，约8分钟后析出大量白色沉淀物，溶液体系流动性变差，将沉淀物进行过滤，得到的固体粉末干燥后，其扫描电镜照片如图9所示。α-生育酚粉末颗粒呈现出不规则的片状晶体或其团聚体。
实施例6(d-α-生育酚微球的化学稳定性试验)
对实施例1制备得到的d-α-生育酚微球及d-α-生育酚进行加速条件下的稳定性试验比较，条件为：40℃/75％相对湿度，结果如表1-2所示。
表1是d-α-生育酚油本身在加速试验条件(40℃/75％相对湿度)下的含量变化；
表1.d-α-生育酚油在加速条件下的含量变化
Figure PCTCN2020085744-appb-000002
表2是实施例1得到的d-α-生育酚微球在加速试验条件(40℃/75％相对湿度)下的含量变化；
表2.d-α-生育酚微球在加速条件下的含量变化
Figure PCTCN2020085744-appb-000003
含量采用HPLC测定，含量的计算方法为外标法。d-α-生育酚油中α-生育酚的初始含量为96.6％，在加速试验条件下(40℃/75％相对湿度)，6个 月后，α-生育酚的含量下降为93.6％。d-α-生育酚微球中α-生育酚的初始含量为86.4％，6个月后，α-生育酚含量仍然高达86.5％。可见，d-α-生育酚微球中α-生育酚含量基本不变，表现出了优异的化学稳定性。
实施例7(dl-α-生育酚微球及二氧化硅吸附的dl-α-生育酚醋酸酯粉在大鼠体内的血药浓度比较，剂量：80mg/kg)
实验试剂：实施例3中制备得到的dl-α-生育酚微球，其中dl-α-生育酚的含量为87.5％；市售二氧化硅吸附的dl-α-生育酚醋酸酯粉，购买自浙江新和成股份有限公司，其中dl-α-生育酚醋酸酯的含量为51.1％；不含维生素E的AIN-G93饲料，购于帆泊生物科技有限公司。
试样配制：将上述dl-α-生育酚微球和二氧化硅吸附的dl-α-生育酚醋酸酯粉分别悬浮于0.5％羧甲基纤维素钠+0.5％十二烷基硫酸钠的水溶液中。
实验方案如下：
动物种属：SD雄性大鼠共12只，随机分为2组；
给药剂量：折合成80mg/kg dl-α-生育酚；
给药形式：以悬浮剂形式灌胃给药
实验过程：
(1)连续喂食一周不含维生素E的饲料；
(2)禁食12小时，单次灌胃给药；
(3)给药后4小时恢复喂食不含维生素E的饲料；
(4)采血时间点：0，1，2，3，4，6，8，10，24小时(采血方式为眼眶后静脉丛取血)
血浆处理方式：100μL血浆样品+200μL乙醇(1％wt/vol抗坏血酸)+1mL正己烷，涡旋1min，离心(5min，10000rpm)；取0.8mL正己烷溶液，N 2吹干，重新用200μL乙醇复溶，涡旋1min，HPLC测试。
不同时间点的α-生育酚血药浓度结果如表3所示。
表3.α-生育酚在不同时间点的血药浓度变化
Figure PCTCN2020085744-appb-000004
Figure PCTCN2020085744-appb-000005
由此可见，在相同剂量下，本发明制备的dl-α-生育酚微球的最大血药浓度可以达到12.9μg/mL，而喂食市售二氧化硅吸附的dl-α-生育酚醋酸酯粉二氧化硅吸附的dl-α-生育酚醋酸酯粉，其最大血药浓度仅为8.3μg/mL。并且，在任一时间点，相比市售二氧化硅吸附的dl-α-二氧化硅吸附粉，使用本发明的dl-α-生育酚微球能够明显地提高血浆中的生育酚浓度。
实施例8(d-α-生育酚微球及d-α-生育酚醋酸酯粉在大鼠体内的血药浓度比较，剂量：80mg/kg)
实验试剂：实施例1中制备得到的d-α-生育酚微球，其中d-α-生育酚的含量为86.4％；市售的食品级d-α-生育酚醋酸酯粉，购买自丰益春之谷生物科技有限公司，其中d-α-生育酚醋酸酯的含量为50.5％；不含维生素E的AIN-G93饲料，购于帆泊生物科技有限公司。
试样配制：将上述d-α-生育酚微球和d-α-生育酚醋酸酯粉分别悬浮于0.5％羧甲基纤维素钠+0.5％十二烷基硫酸钠的水溶液中。
实验方案如下：
动物种属：SD雄性大鼠共12只，随机分为2组；
给药剂量：折合成80mg/kg d-α-生育酚；
给药形式：以悬浮剂形式灌胃给药
实验过程：
(1)连续喂食一周不含维生素E的饲料；
(2)禁食12小时，单次灌胃给药；
(3)给药后4小时恢复喂食不含维生素E的饲料；
(4)采血时间点：0，1，2，3，4，6，8，10，24小时(采血方式为眼眶后静脉丛取血)
血浆处理方式：100μL血浆样品+200μL乙醇(1％wt/vol抗坏血酸)+1mL正己烷，涡旋1min，离心(5min，10000rpm)；取0.8mL正己烷溶液，N 2吹干，重新用200μL乙醇复溶，涡旋1min，HPLC测试。
不同时间点的α-生育酚血药浓度结果如表4所示。d-α-生育酚微球，其最大血药浓度C max为14.0μg/mL，而d-α-生育酚醋酸酯粉的最大血药浓度C max为10.8μg/mL。
表4.α-生育酚在不同时间点的血药浓度变化
Figure PCTCN2020085744-appb-000006
Figure PCTCN2020085744-appb-000007
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (14)

  1. 一种α-生育酚的微球，其特征在于：包含α-生育酚和甜菜碱，其中，α-生育酚的质量分数为50％-90％；甜菜碱的质量分数为10％-50％。
  2. 如权利要求1所述的α-生育酚的微球，其特征在于：粒径分布在10-500微米。
  3. 如权利要求1所述的α-生育酚的微球，其特征在于：粒径分布为50-200微米。
  4. 如权利要求1所述的α-生育酚的微球，其特征在于：所述α-生育酚，选自天然α-生育酚和合成生育酚。
  5. 如权利要求4所述的天然α-生育酚的微球，其特征在于：以2θ角度表示的X-射线粉末衍射在衍射角为3.8±0.2，5.7±0.2，7.6±0.2，9.6±0.2，11.5±0.2，13.5±0.2，16.4±0.2，17.4±0.2，21.3±0.2度处具有特征峰；优选地，还在15.3±0.2，16.4±0.2，19.5±0.2度处具有特征峰；更优选地，其具有图1所示的X-射线粉末衍射图。
  6. 如权利要求4所述的天然α-生育酚的微球，其特征在于：所述微球通过差式扫描量热法测定，在44±2℃处具有吸热峰，微球熔化起始温度为106±2℃，最大峰值为107℃；优选地，其具有图2所示的差示扫描量热分析图。
  7. 如权利要求4所述的天然α-生育酚的微球，其特征在于：所述微球通过采用傅里叶变换红外光谱仪得到的红外吸收光谱定性，采用下面所述的重要波数定性：3341cm -1、2928cm -1、2866cm -1、1651cm -1、1464cm -1、1416cm -1、1386cm -1、1336cm -1、1264cm -1、1228cm -1、1170cm -1、1094cm -1、930cm -1、892cm -1、728cm -1、641cm -1；优选地，具有图3所示的红外光谱。
  8. 如权利要求4所述的天然α-生育酚的微球，其特征在于：所述微球通过采用激光拉曼光谱仪得到的拉曼光谱定性，采用下面所述的重要波数定性：2923cm -1、2869cm -1、1579cm -1、1456cm -1、1335cm -1、783cm -1、589cm -1、485cm -1；优选地，具有图4所示的拉曼光谱图。
  9. 权利要求1-8中任一项所述α-生育酚的微球的制备方法，其特征在于包括如下步骤：将α-生育酚和甜菜碱共同溶解于有机溶剂中，搅拌溶清，冷却至-30℃-0℃，析出白色沉淀物，离心，干燥沉淀物，得到所述α-生育酚的微球。
  10. 如权利要求9所述的制备方法，其特征在于：所用α-生育酚的纯度大于等于90％，优选地，所用α-生育酚的纯度大于等于95％。
  11. 如权利要求9所述的制备方法，其特征在于：所用有机溶剂为甲醇或乙醇。
  12. 权利要求1-8中任一项所述α-生育酚的微球在制备动物饲料或人类营养保健品中的用途。
  13. 如权利要求12所述的用途，其特征在于：所述动物饲料用于提高动物的血浆或组织中的α-生育酚浓度，增强动物的免疫力、提高动物繁殖中的产仔数和动物幼仔的生命力、改善动物肉的品质。
  14. 如权利要求12所述的用途，其特征在于：所述人类营养保健品用于提高人的血浆或组织中的α-生育酚浓度，提高抗氧化作用，提高人体免疫力、美白、淡斑、抗衰老以及在用于生育过程中的需求。
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