WO2020253710A1 - 一种辅酶q10透明水分散液的制备方法 - Google Patents

一种辅酶q10透明水分散液的制备方法 Download PDF

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WO2020253710A1
WO2020253710A1 PCT/CN2020/096517 CN2020096517W WO2020253710A1 WO 2020253710 A1 WO2020253710 A1 WO 2020253710A1 CN 2020096517 W CN2020096517 W CN 2020096517W WO 2020253710 A1 WO2020253710 A1 WO 2020253710A1
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coenzyme
preparation
emulsifier
aqueous dispersion
water
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French (fr)
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乐园
钟杰
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宁波海奇合昇环能科技有限公司
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    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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

Definitions

  • the invention relates to the field of biotechnology. More specifically, it relates to a method for preparing a transparent aqueous dispersion of Coenzyme Q10.
  • Coenzyme Q10 is an insoluble antioxidant molecule that plays an important role in the mitochondrial respiratory chain. It is called an excellent antioxidant compound and has high biological value, but its bioavailability is poor, and its synthesis rate Decrease gradually with aging. Due to low solubility and high permeability, CoQ10 is classified as a class II drug according to the biopharmaceutical classification system. In order to improve the bioavailability of CoQ10, various preparations for improving the oral bioavailability of CoQ10 have been studied, including oil solutions , Solid dispersions, complexes and nanoemulsions.
  • Nanoemulsion is a dispersion of two immiscible solutions stabilized with appropriate surfactants. It has high optical transparency, physical stability and easy digestibility. It is an effective delivery system that can be used to absorb, protect and release various A functional food ingredient. The smaller particle size can not only lead to the long-term physical stability of the nanoemulsion, but also improve the bioavailability of CoQ10. From the perspective of improving oral bioavailability and reducing production costs, oil-in-water (O/W) nanoemulsions are one of the excellent delivery methods for CoQ10.
  • the existing technology on coenzyme Q10 nanoemulsion mostly uses the dissolution of coenzyme Q10 in solvent oil as the oil phase, such as medium-chain fatty acid glycerides or vegetable oil.
  • solvent oil such as medium-chain fatty acid glycerides or vegetable oil.
  • solvent oils have low solubility for coenzyme Q10, which limits the content of coenzyme Q10 in the nanoemulsion.
  • high-speed shearing method, high-pressure homogenization method, etc. are used to prepare coenzyme Q10 nanoemulsion with better stability. However, these methods are difficult to achieve industrial scale-up and can only be produced in small batches.
  • the object of the present invention is to provide a method for preparing a transparent aqueous dispersion of coenzyme Q10, which improves the problem of poor water solubility of coenzyme Q10, increases the content of coenzyme Q10 in the aqueous dispersion, and reduces the coenzyme Q10 emulsion in the aqueous dispersion
  • the particle size (less than 100nm) of Coenzyme Q10 improves the bioavailability and stability of Coenzyme Q10; in addition, the method is very easy to scale up and can be industrially produced.
  • the present invention adopts the following technical solutions:
  • a preparation method of coenzyme Q10 transparent water dispersion including the following steps:
  • the obtained molten mixture is mixed with water, and the mixture is uniformly stirred to obtain the coenzyme Q10 transparent aqueous dispersion.
  • the heating and melting temperature is 50-60°C.
  • the emulsifier is selected from Tween 20, Tween 80, Span 80, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, poloxamer, fatty acid monoglyceride, soybean phospholipid, egg yolk One or more of lecithin.
  • the aforementioned emulsifier has a strong ability to cooperate with coenzyme Q10 in the oil phase, which helps to control the particle size and stability of the coenzyme Q10 emulsion in the prepared dispersion.
  • the mixture also includes a co-emulsifier, the co-emulsifier is selected from one or more of absolute ethanol, 1,2-propylene glycol, glycerol, n-butanol, polyethylene glycol 400 Kind.
  • the weight ratio of the emulsifier to the co-emulsifier is 1:5-5:1.
  • the weight ratio of the emulsifier to the co-emulsifier is 1:4-4:1.
  • the weight ratio of the emulsifier to the co-emulsifier is 1:3-3:1.
  • exemplary optional weight ratios of emulsifier and co-emulsifier include but are not limited to 1:2-2:1, 1:1, etc.
  • the weight ratio of emulsifier to co-emulsifier also affects the stability and particle size of the resulting aqueous dispersion.
  • the ratio of the two is within the aforementioned limited range, the stability of the aqueous dispersion is better, and the particle size can be controlled between 20-60nm, and the smaller the aforementioned ratio range, the better the stability, that is, 1:2-2
  • the stability in the range of :1 is better than the overall stability in the range of 1:5-5:1.
  • the weight ratio of the coenzyme Q10 to the emulsifier is 1:10-1:0.5.
  • the weight ratio of the emulsifier to the co-emulsifier is the weight ratio of the coenzyme Q10 to the emulsifier including but not limited to 1:10-1:1, 1:10-1:3, 1: 10-1:5, 1:5-1:0.5, 1:5-1:1, 1:5-1:3, 1:3-1:0.5 or 1:3-1:1 etc.
  • the weight ratio of the two within this range can minimize toxic and side effects while ensuring the stability of the Coenzyme Q10 transparent water dispersion.
  • the temperature at which the molten mixture is mixed with water is 25-100°C.
  • the temperature at which the molten mixture is mixed with water is 40-70°C.
  • the mixing and stirring are performed in a supergravity rotating bed, a microchannel reactor, a stirred reactor or an ultrasonic generator.
  • the mass ratio of the molten mixture and the water is 1:10-1:200.
  • the feed volume ratio of the molten mixture to water is 1:10-1:200, preferably 1:20- 1:100, more preferably 1:20-1:80.
  • the rotation speed of the high gravity rotating bed is 500-2800 r/min, preferably 1500-2500 r/min.
  • the stirring rate of the stirred reactor is 100-2000 r/m, preferably 500-1000 r/m.
  • the ultrasonic generator power is 600w-2400w, preferably 900w-1800w.
  • Any range recorded in the present invention includes an end value and any value between the end values, and any sub-range formed by the end value or any value between the end values.
  • the raw materials in the present invention can be purchased commercially, and the equipment used in the present invention can be made with conventional equipment in the field or with reference to the prior art in the field.
  • the preparation method of the coenzyme Q10 transparent aqueous dispersion improves the problem of poor water solubility of coenzyme Q10, increases the content of coenzyme Q10 in the aqueous dispersion, and makes the particle size of the coenzyme Q10 emulsion in the aqueous dispersion less than 100 nm, and at the same time increases
  • the bioavailability and stability of coenzyme Q10 further, in the preparation method, by limiting the addition amount relationship between the components, the stability of the coenzyme Q10 is better improved, and the particle size of the emulsion Control between 20-60nm.
  • the method is simple, easy to implement, low energy consumption, high efficiency, low cost, and is very easy to scale up, achieving the goal of industrial production.
  • Figure 1 shows the particle size distribution diagram of the Coenzyme Q10 aqueous dispersion prepared in Example 1 of the present invention.
  • Figure 2 shows the drug content of the Coenzyme Q10 aqueous dispersion prepared in Example 1 of the present invention.
  • Figure 3 shows the transmittance diagram of the Coenzyme Q10 aqueous dispersion prepared in Example 1 of the present invention.
  • Figure 4 shows the morphology of the aqueous dispersions of Coenzyme Q10 prepared in Example 1, Comparative Example 1 and Comparative Example 2 of the present invention after being placed at room temperature for 30 days.
  • Figure 5 shows a scanning electron micrograph of the Coenzyme Q10 aqueous dispersion prepared in Example 3 of the present invention.
  • the nanoemulsion prepared in this example has a clear and transparent appearance, and the average particle size is about 22.5 nm.
  • a laser particle size analyzer is used to test the particle size of the aqueous dispersion; an ultraviolet-visible spectrophotometer is used to test the transmittance of the aqueous dispersion; and a high performance liquid chromatography is used to test the drug content of the aqueous dispersion. Each sample is tested three times.
  • the nanoemulsion prepared in this example has a clear and transparent appearance, with an average particle size of 35 nm.
  • the stability test was carried out according to the method of Example 1. After being placed at room temperature, 4°C ⁇ 2°C, and 40°C ⁇ 2°C for 30 days, the solution was still transparent. The result of placing it at room temperature for 30 days is shown in Figure 4.
  • the stability test was carried out according to the method of Example 1.
  • the nanoemulsion prepared in this example was placed at room temperature, 4°C ⁇ 2°C, and 40°C ⁇ 2°C for 30 days.
  • the appearance was clear and transparent, and the average particle size was 50-60nm.
  • the scanning electron microscope picture is shown in Figure 5.
  • the stability test was carried out according to the method of Example 1.
  • the nanoemulsion prepared in this comparative example has a clear and transparent appearance, and the appearance is clear and transparent after being placed at room temperature, 4°C ⁇ 2°C, and 40°C ⁇ 2°C for 30 days.
  • the particle size is 40 -50nm.
  • the stability test was carried out according to the method of Example 1.
  • the nanoemulsion prepared in this example has a clear and transparent appearance, and the appearance is clear and transparent after being placed at room temperature, 4°C ⁇ 2°C, and 40°C ⁇ 2°C for 30 days, with an average particle size It is 50-60nm.
  • the stability test was carried out according to the method of Example 1.
  • the nanoemulsion prepared in this example has a clear and transparent appearance, and the appearance is clear and transparent after being placed at room temperature, 4°C ⁇ 2°C, and 40°C ⁇ 2°C for 30 days, with an average particle size It is 40-50nm.
  • Example 2 Repeat Example 2 with the difference that the amount of glycerol was changed to 5.625g, and other conditions were unchanged, to prepare an aqueous dispersion of Coenzyme Q10, the content of Q10 was 8.36mg/ml, and the appearance of the nanoemulsion prepared in this example was clear , The average particle size is 50-60nm, and the appearance is clear and transparent after being placed at room temperature, 4°C ⁇ 2°C, 40°C ⁇ 2°C for 30 days.
  • Example 2 the difference is that the amount of Coenzyme Q10 is changed to 5g, and other conditions remain unchanged, the prepared Coenzyme Q10 aqueous dispersion Q10 content is 6.19mg/ml, and the nanoemulsion prepared in this example has a clear appearance and average particle size. The diameter is 40-50nm. And the appearance is clear and transparent after standing at room temperature, 4°C ⁇ 2°C, 40°C ⁇ 2°C for 30 days.
  • Example 1 was repeated, except that the mixed oil phase and water were mixed under high-speed shearing conditions of 20000 rpm for 10 minutes to obtain an aqueous dispersion of Coenzyme Q10.
  • the nanoemulsion prepared in this comparative example has a turbid appearance and an average particle diameter of 151.6 nm.
  • the stability test was performed according to the method of Example 1. After being left at room temperature for 30 days, the solution was turbid and the background could not be seen clearly. The result is shown in FIG. 4.
  • Example 2 the difference is that the rotation speed of the supergravity rotating bed is changed to 400 rpm, and other conditions remain unchanged.
  • the particle size of the nanoemulsion in the obtained aqueous dispersion is about 261.5 nm, and the transparency of the aqueous dispersion is poor.
  • the stability test was performed according to the method of Example 1. After being left at room temperature for 30 days, the solution was turbid and the background could not be seen clearly. The result is shown in Figure 4.

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Abstract

一种辅酶Q10透明水分散液的制备方法，包括如下步骤：将包括辅酶Q10和乳化剂的混合物加热熔化，得熔融态的混合物；将得到的熔融态的混合物与水混合，经搅拌均匀后，得所述辅酶Q10透明水分散液。该制备方法改善了辅酶Q10水溶性差的问题，提高了水分散液中辅酶Q10的含量、降低了水分散液中辅酶Q10乳液的粒径(小于100nm)，改善了辅酶Q10的生物利用度和稳定性；此外，该方法非常容易放大，可工业化生产。

Description

一种辅酶Q10透明水分散液的制备方法 技术领域
本发明涉及生物技术领域。更具体地，涉及一种辅酶Q10透明水分散液的制备方法。
背景技术
辅酶Q10(CoQ10)是一种不溶性抗氧化剂分子，在线粒体呼吸链中起重要作用，被称为优异的抗氧化剂化合物，具有很高的生物学价值，但生物利用度较差，并且其合成速率随着衰老逐渐降低。由于低溶解度和高渗透性，CoQ10根据生物药物分类系统被归类为II类药物，为了提高CoQ10的生物利用度，已经研究了用于改善CoQ10的口服生物利用度的各种制剂，包括油溶液，固体分散体，络合物和纳米乳液等。
纳米乳液是使用适当的表面活性剂稳定的两种不混溶液体的分散体，具有高光学透明度，物理稳定性和易消化性，是一种有效的输送系统，可用于吸收、保护和释放各种功能性食品成分。较小的粒径不仅可以导致纳米乳液的长期物理稳定性，还可以提高CoQ10的生物利用度。从改善口服生物利用度和降低生产成本的角度看，水包油(O/W)纳米乳液是CoQ10的优异输送方法之一。
目前关于辅酶Q10纳米乳液的现有技术多采用将辅酶Q10溶解在溶剂油作为油相，例如中链脂肪酸甘油酯或者植物油。但常用溶剂油脂对辅酶Q10溶解度较低，限制了纳米乳液中辅酶Q10的含量。另外，现有技术中还有采用高速剪切法、高压均质法等制备得到稳定性较好的辅酶Q10纳米乳液，然而，这些方法难以实现工业放大，只能小批量的生产。
发明内容
本发明的目的在于提供一种辅酶Q10透明水分散液的制备方法，该制备方法改善了辅酶Q10水溶性差的问题，提高了水分散液中辅酶Q10的含量、降低了水分散液中辅酶Q10乳液的粒径(小于100nm)，改善了辅酶Q10的生物利用度和稳定性；此外，该方法非常容易放大，可工业化生产。
为达到上述目的，本发明采用下述技术方案：
一种辅酶Q10透明水分散液的制备方法，包括如下步骤：
将包括辅酶Q10和乳化剂的混合物加热熔化，得熔融态的混合物；
将得到的熔融态的混合物与水混合，经搅拌均匀后，得所述辅酶Q10透明水分散液。
可选地，所述加热融化的温度为50-60℃。
可选地，所述乳化剂选自吐温20、吐温80、司盘80、聚氧乙烯氢化蓖麻油、蓖麻油聚氧乙烯醚、泊洛沙姆、脂肪酸单甘油脂、大豆磷脂、蛋黄卵磷脂中的一种或多种。前述乳化剂与油相辅酶Q10配合能力强，有助于控制制备得到的分散液中辅酶Q10乳液的粒径及稳定性。
可选地，所述混合物中还包括助乳化剂，所述助乳化剂选自无水乙醇、1,2-丙二醇、 丙三醇、正丁醇、聚乙二醇400中的一种或多种。
可选地，所述乳化剂与助乳化剂的重量比为1:5-5:1。
可选地，所述乳化剂与助乳化剂的重量比为1:4-4:1。
可选地，所述乳化剂与助乳化剂的重量比为1:3-3:1。
进一步地，示例性可选地乳化剂与助乳化剂的重量比包括但不限于为1:2-2:1、1:1等。
乳化剂与助乳化剂的重量比也影响得到的水分散液的稳定性及粒径。两者的比例在前述限定的范围内时水分散液的稳定性更好，且能控制粒径在20-60nm之间，且前述比例范围越小稳定性越好，也即1:2-2:1范围内的稳定性优于1:5-5:1范围内的整体稳定性。
可选地，所述辅酶Q10与乳化剂的重量比为1:10-1:0.5。进一步可选的，所述乳化剂与助乳化剂的重量比为所述辅酶Q10与乳化剂的重量比包括但不限于为1:10-1:1、1:10-1:3、1:10-1:5、1:5-1:0.5、1:5-1:1、1:5-1:3、1:3-1:0.5或1:3-1:1等。限定在该范围内的两者的重量比能够在最大程度上减少毒副伤害的同时保证辅酶Q10透明水分散液的稳定性。
可选地，所述熔融态的混合物与水混合的温度为25-100℃。
可选地，所述熔融态的混合物与水混合的温度为40-70℃。
可选地，所述混合和搅拌均在超重力旋转床、微通道反应器、搅拌式反应器或超声波发生器中进行。采用在超重力旋转床、微通道反应器、搅拌式反应器或超声波发生器中混合，一方面能够实现获得粒度小且均一的纳米乳液，另一方面采用该混合手段有助于提高所得透明水分散液的稳定性。
可选地，所述熔融态的混合物与水混合的质量比为1:10-1:200。
可选地，当所述混合在超重力旋转床或微通道反应器中进行时，所述熔融态的混合物与水的进料体积比为1:10-1:200，优选为1:20-1:100，更优选为1:20-1:80。
可选地，当所述混合在超重力旋转床中进行时，所述超重力旋转床的转速为500-2800r/min，优选为1500-2500r/min。
可选地，当所述混合在搅拌式反应器中进行时，搅拌式反应器搅拌速率为100-2000r/m，优选500-1000r/m。
可选地，当所述混合在超声波发生器中进行时，超声波发生器功率600w-2400w，优选900w-1800w。
本发明所记载的任何范围包括端值以及端值之间的任何数值以及端值或者端值之间的任意数值所构成的任意子范围。
如无特殊说明，本发明中的各原料均可通过市售购买获得，本发明中所用的设备可采用所属领域中的常规设备或参照所属领域的现有技术进行。
本发明的有益效果如下：
本发明提供的辅酶Q10透明水分散液的制备方法改善了辅酶Q10水溶性差的问题，提高了水分散液中辅酶Q10的含量、使得该水分散液中辅酶Q10乳液粒径小于100nm，同时提高了辅酶Q10的生物利用度和稳定性；进一步地，该制备方法中，通过对各组分间的添加量关系的限定，从而更好的改善了该辅酶Q10的稳定性，且将该乳液粒径控制在20-60nm之间。此外，该方法简单，易于实现，能耗少，效率高，成本低，而且非常容易放大，达到工业化生产的发明目标。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细的说明。
图1示出本发明实施例1制备得到的辅酶Q10水分散液的粒径分布图。
图2示出本发明实施例1制备得到的辅酶Q10水分散液的药物含量图。
图3示出本发明实施例1制备得到的辅酶Q10水分散液的透射率图。
图4分别示出本发明实施例1、对比例1和对比例2制备得到的辅酶Q10水分散液在室温放置30天后的形态。
图5示出本发明实施例3制备得到的辅酶Q10水分散液的扫描电镜图片。
具体实施方式
为了更清楚地说明本发明，下面结合优选实施例和附图对本发明做进一步的说明。附图中相似的部件以相同的附图标记进行表示。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
实施例1
称取6.75g辅酶Q10，27g聚氧乙烯氢化蓖麻油，6.75g 1,2-丙二醇加热至60℃熔融并涡旋振荡混合均匀，得到混合溶液。超重力旋转床转速为2000rpm，混合油相以3ml/min、提前预热的纯化水以240ml/min进料，控制体系温度为60℃，待混合溶液进料完毕后，关闭超重力旋转床，即得到辅酶Q10水分散液，Q10含量为7.03mg/ml。
本实施例制得的纳米乳液外观澄清透明，平均粒径为22.5nm左右。
稳定性测试方法：
取上述制备得到的水分散液样品置于棕色螺口瓶内，在室温、4℃±2℃、40℃±2℃条件下放置一个月，于7天、14天、30天取样，用马尔文激光粒度仪测试水分散液粒径；用紫外可见光分光光度计测试水分散液透射率；用高效液相色谱测试水分散液药物含量。每个样品测试三次。
在室温、4℃±2℃、40℃±2℃条件下放置30天后，辅酶Q10水分散液粒径(如图1所示)、药物含量(如图2所示)和透射率(如图3所示，图3中，4条曲线接近重合)均无明显变化，稳定性较高。
实施例2
称取6.75g辅酶Q10，33.75g吐温20，16.87g丙三醇加热至60℃熔融并涡旋振荡混合均匀，得到混合溶液。超重力旋转床转速为1500pm，混合油相以5ml/min、提前预热的纯化水以250ml/min进料，控制体系温度为50℃，待混合溶液进料完毕后，关闭超重力旋转床，即得到辅酶Q10水分散液，Q10含量为8.36mg/ml。
本实施例制得的纳米乳液外观澄清透明，平均粒径为35nm。按实施例1的方法进行稳定性测试，在室温、4℃±2℃、40℃±2℃条件下放置30天后，溶液依然透明，其在室温下放置30天的结果如图4所示。
实施例3
称取9g辅酶Q10，45g吐温20，15g丙三醇加热至60℃熔融并涡旋振荡混合均匀，得到混合溶液。混合油相以6ml/min、提前预热的纯化水以360ml/min进料速度通入微通道 反应器，控制体系温度为40℃，待混合溶液进料完毕后，即得到辅酶Q10水分散液，Q10含量为10.97mg/ml。
按实施例1的方法进行稳定性测试，本实施例制得的纳米乳液在室温、4℃±2℃、40℃±2℃条件下放置30天后外观澄清透明，平均粒径为50-60nm，其扫描电镜图片如图5所示。
实施例4
称取0.69g辅酶Q10，2.07g聚氧乙烯氢化蓖麻油加热至60℃熔融并涡旋振荡混合均匀，得到混合溶液。控制磁力搅拌速度800r/min，水浴温度为50℃，将混合油相加入100ml水中，搅拌10min，即得到辅酶Q10水分散液，浓度为6.9mg/ml。
按实施例1的方法进行稳定性测试，本对比例制得纳米乳液外观澄清透明，且在室温、4℃±2℃、40℃±2℃条件下放置30天后外观澄清透明，粒径在40-50nm。
实施例5
称取0.23g辅酶Q10，1.5g卵磷脂，1g聚乙二醇400加热至60℃熔融并涡旋振荡混合均匀，得到混合溶液。将上述混合溶液加入100ml纯化水中，50℃水浴，以900W的功率超声10min得到辅酶Q10水分散液，Q10含量为2.3mg/ml。
按实施例1的方法进行稳定性测试，本实施例制得的纳米乳液外观澄清透明，且在室温、4℃±2℃、40℃±2℃条件下放置30天后外观澄清透明，平均粒径为50-60nm。
实施例6
称取6.75g辅酶Q10，20.25g聚氧乙烯氢化蓖麻油，加热至60℃熔融并涡旋振荡混合均匀，得到混合溶液。超重力旋转床转速为1000rpm，混合油相以5ml/min、提前预热的纯化水以300ml/min进料，控制体系温度为50℃，待混合溶液进料完毕后，关闭超重力旋转床，即得到辅酶Q10水分散液Q10含量为4.5mg/ml。
按实施例1的方法进行稳定性测试，本实施例制得的纳米乳液外观澄清透明，且在室温、4℃±2℃、40℃±2℃条件下放置30天后外观澄清透明，平均粒径为40-50nm。
实施例7
重复实施例2，区别在于，将丙三醇的量改为5.625g，其余条件不变，制备得到辅酶Q10水分散液，Q10含量为8.36mg/ml，本实施例制得的纳米乳液外观澄清，平均粒径为50-60nm，且在室温、4℃±2℃、40℃±2℃条件下放置30天后外观澄清透明。
实施例8
重复实施例2，区别在于，将辅酶Q10的量改为5g，其余条件不变，制备得到辅酶Q10水分散液Q10含量为6.19mg/ml，本实施例制得的纳米乳液外观澄清，平均粒径为40-50nm。且在室温、4℃±2℃、40℃±2℃条件下放置30天后外观澄清透明。
对比例1
重复实施例1，区别在于，将混合油相与水在20000rpm高速剪切条件下混合10分钟，得到辅酶Q10水分散液。本对比例制得的纳米乳液外观浑浊，平均粒径为151.6nm。按实施例1的方法进行稳定性测试，在室温放置30天后，溶液浑浊，无法看清其后的背景，结果如图4所示。
对比例2
重复实施例2，区别在于，将超重力旋转床的转速改为400rpm，其余条件不变，得到的水分散液中纳米乳液粒径为261.5nm左右，且水分散液透明度较差。按实施例1的方法 进行稳定性测试，在室温放置30天后，溶液浑浊，无法看清其后的背景，结果如图4所示。
显然，本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定，对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动，这里无法对所有的实施方式予以穷举，凡是属于本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之列。

Claims (10)

  1. 一种辅酶Q10透明水分散液的制备方法，其特征在于，包括如下步骤：
    将包括辅酶Q10和乳化剂的混合物加热熔化，得熔融态的混合物；
    将得到的熔融态的混合物与水混合，经搅拌均匀后，得所述辅酶Q10透明水分散液。
  2. 根据权利要求1所述的制备方法，其特征在于，所述加热融化的温度为50-60℃。
  3. 根据权利要求1所述的制备方法，其特征在于，所述乳化剂选自吐温20、吐温80、司盘80、聚氧乙烯氢化蓖麻油、蓖麻油聚氧乙烯醚、泊洛沙姆、脂肪酸单甘油脂、大豆磷脂、蛋黄卵磷脂中的一种或多种。
  4. 根据权利要求1所述的制备方法，其特征在于，所述混合物中还包括助乳化剂，所述助乳化剂选自无水乙醇、1,2-丙二醇、丙三醇、正丁醇、聚乙二醇400中的一种或多种。
  5. 根据权利要求4所述的制备方法，其特征在于，所述乳化剂与助乳化剂的重量比为1:5-5:1，优选为1:4-4:1，更优选为1:3-3:1。
  6. 根据权利要求1所述的制备方法，其特征在于，所述辅酶Q10与乳化剂的重量比为1:10-1:0.5，优选为1:5-1:1。
  7. 根据权利要求1所述的制备方法，其特征在于，所述熔融态的混合物与水混合的温度为25-100℃，优选为40-70℃。
  8. 根据权利要求1所述的制备方法，其特征在于，所述混合和搅拌均在超重力旋转床、微通道反应器、搅拌式反应器或超声波发生器中进行。
  9. 根据权利要求1所述的制备方法，其特征在于，所述熔融态的混合物与水混合的质量比为1:10-1:200。
  10. 根据权利要求8所述的制备方法，其特征在于，当所述混合在超重力旋转床或微通道反应器中进行时，所述熔融态的混合物与水的进料体积比为1:10-1:200，优选为1:20-1:100；优选地，所述超重力旋转床的转速为500-2800r/min，更优选为1500-2500r/min。
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