Temperature-responsive ultrathin shell lipid capsules, methods of making and using the same

Abstract

The application discloses a preparation method and product of a temperature-responsive ultrathin shell lipid capsule and application, and discloses a temperature intelligent response lipid capsule prepared by wrapping gel oil with an ultrathin hydrogel shell, wherein high-melting-point lipids with strong gelation capacity are dispersed into liquid vegetable oil as gel factors to form an oil gel with a dense network structure. The application introduces high-melting-point lipids, uses the strong oil holding capacity of the high-melting-point lipids to form a three-dimensional crystalline network structure with liquid oil to fix the liquid oil and form an oil gel to protect fat-soluble active substances, and improves the slow-release performance of the liquid vegetable oil. The application has universality and is generally applicable to the preparation of oil gels of solid lipids to protect fat-soluble active substances.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of personal care, and particularly relates to a preparation method and product of a super-thin shell lipid capsule with high loading and temperature response prepared by a coaxial co-extrusion microfluidic device, and application thereof. BACKGROUND

[0002] The fat-soluble active ingredients are various, mainly including unsaturated fatty acids (such as EPA, DHA), carotenoids (such as beta-carotene, astaxanthin), hydrophobic polyphenols (such as resveratrol, quercetin), hydrophobic vitamins (such as vitamin A, vitamin E) and the like. These fat-soluble active ingredients have high application value in the fields of functional foods and personal care products.

[0003] However, the fat-soluble active ingredients have poor water solubility, low utilization rate, relatively easy volatilization and oxidation decomposition, and poor stability, which greatly limits their application value. Gel oil is a kind of semi-solid viscoelastic system obtained by binding liquid oil in a certain network structure through crystallization or self-assembly of a small amount of gel factor, so that the liquid oil loses fluidity. There are various construction methods for gel oil, and crystallization is the simplest method.

[0004] In addition, the crystalline gel oil has a dense crystalline structure, and thus can effectively isolate oxygen and water molecules and has temperature response, so as to provide a dense protective network for the fat-soluble active substances and can intelligently respond to temperature. Natural wax has been proved to be one of the most effective crystallization factors, which can be used to improve the structure of solid fat and has strong oil binding capacity. When the wax is dispersed in the oil, the wax captures the liquid oil by crystallization, and under the weak interaction of non-covalent bonds, the crystals are aggregated to form one-dimensional needle-shaped, linear and strip-shaped aggregates, which are then connected to each other to form a three-dimensional network structure, thereby preventing the flow of lipophilic liquids and making the whole system gel.

[0005] Due to the poor water solubility and stability of the gel oil, its application in the field of active material carriers is greatly limited, and further optimization is needed. Capsule technology is a common means for embedding active substances, which is a technology for preparing substances with core-shell encapsulation structure by using polymer as wall material to embed small liquid, solid and gaseous substances. In recent years, the emulsion template method is often used to prepare porous calcium alginate capsules. This method mainly uses one-pot oil-water two-phase to produce water-in-oil calcium alginate droplets to produce capsules, but the loading rate of fat-soluble active materials is not high and the size cannot be accurately controlled. In addition, some chemical methods for preparing microcapsules, such as interfacial polymerization and in-situ polymerization, have harsh reaction conditions, are not easy to produce, and have uneven particle size. Therefore, it is of great guiding significance to seek a fat-soluble active material carrier with high loading, super stability, and precise control of size and component distribution for the fields of functional foods and personal care. SUMMARY

[0006] This section is intended to summarize some aspects of the embodiments of the present application and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section as well as in the abstract of the specification and the title of the application in order to avoid obscuring the purpose of the section, the abstract of the specification and the title of the application as such simplifications or omissions are not intended to limit the scope of the present application.

[0007] In view of the above and / or problems existing in the prior art, the present application is proposed.

[0008] Therefore, the purpose of the present application is to overcome the deficiencies in the prior art, and to provide a preparation method of temperature-responsive ultra-thin shell lipid capsules.

[0009] To solve the above technical problems, the present application provides the following technical scheme: a preparation method of temperature-responsive ultra-thin shell lipid capsules, comprising,

[0010] Dissolve high-melting-point lipids in liquid vegetable oil, add fat-soluble active substances, heat and melt, cool at room temperature, and obtain an oil gel sample as an internal fluid;

[0011] Add sodium alginate and emulsifiers to deionized water, stir and melt at room temperature, and obtain an external fluid;

[0012] Inject the internal fluid and the external fluid into a coaxial co-extrusion microfluidic device respectively, set the flow rate, heat the internal fluid, and form O / W droplets;

[0013] Drop the O / W droplets into a calcium chloride solution at a certain height, crosslink, and obtain temperature-responsive ultra-thin shell lipid capsules.

[0014] As a preferred scheme of the preparation method of the present application, wherein: the high-melting-point lipids are dissolved in liquid vegetable oil, wherein the high-melting-point lipids are one or more of rice bran wax RBW, sunflower wax SFW, candelilla wax CLW, carnauba wax CW, beeswax BW, palm kernel oil PKO, palm kernel stearin fraction PKS, coconut oil CNO, and palm oil PO; and the liquid vegetable oil is one or more of camellia oil, olive oil, peanut oil, sunflower oil, rapeseed oil, flaxseed oil, fish oil, and corn oil.

[0015] As a preferred scheme of the preparation method of the present application, wherein: the fat-soluble active substances are added, wherein the fat-soluble active substances are one or more of EPA, DHA, beta-carotene, astaxanthin, such as resveratrol, carvacol, vitamin A, vitamin E, coenzyme Q 10 .

[0016] As a preferred scheme of the preparation method, the mass ratio of the high-melting point lipid, the liquid vegetable oil and the fat-soluble active substance is 99:1-97:3.

[0017] As a preferred scheme of the preparation method, the sodium alginate and the emulsifier are added to the deionized water, wherein the emulsifier is at least one of Tween and sucrose ester; the mass ratio of the sodium alginate, the emulsifier and the deionized water is 1-2.5:0.5-2:97.

[0018] As a preferred scheme of the preparation method, the flow rates are set, wherein the flow rate of the outer phase is 100-300 muL / min, and the flow rate of the inner phase is 15-120 muL / min.

[0019] As a preferred scheme of the preparation method, the internal fluid is heated, wherein the heating temperature is 80-85 DEG C.

[0020] As a preferred scheme of the preparation method, the O / W droplets are dropped into the calcium chloride solution at a certain height for cross-linking, wherein the mass of the calcium chloride solution is 1-5 wt%, the wt% is the weight percentage in the total weight of the solution; the calcium chloride solution needs to be heated by a heating pad, the voltage of the heating pad is 120-130 V; the certain height is 8-12 cm, and the cross-linking time is 0.5-2 h.

[0021] Still another object of the present application is to provide a temperature-responsive ultra-thin shell lipid capsule to overcome the deficiencies in the prior art.

[0022] Another object of the present application is to provide the application of the temperature-responsive ultra-thin shell lipid capsule in functional food and personal care to overcome the deficiencies in the prior art.

[0023] The present application has the following advantages:

[0024] (1) The present application introduces high-melting point lipids, which have strong oil holding capacity, and forms a three-dimensional crystalline network structure with liquid oil to fix the liquid oil and form an oil gel to protect the fat-soluble active substance, thereby improving the sustained-release performance of the liquid vegetable oil.

[0025] (2) The present application uses a coaxial co-extrusion microfluidic device to prepare lipid capsules, which can further improve the biocompatibility of the capsules and the sustained-release performance of the fat-soluble active substance. This method can precisely control the size, wall thickness and component positioning, efficiently and stably encapsulate the fat-soluble active substance, and then further air-dry to obtain an ultra-thin shell lipid capsule.

[0026] (3) When the temperature is higher than the melting point of the high melting point lipid, the inner core lipid crystalline network of the lipid capsule collapses, and the hydrogel beads cause changes in the gel structure under the action of changes in the external environment, thereby slowly releasing the embedded oil and fat. The ultra-thin shell lipid capsule prepared by the method has temperature response and slow release performance.

[0027] (4) The present application has universality and is generally applicable to the preparation of oil gels by solid lipids to protect fat-soluble active substances. BRIEF DESCRIPTION OF DRAWINGS

[0028] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed in the embodiment description will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor. Among them:

[0029] Figure 1 The morphology diagram of the oil gel after cooling prepared by different BW contents of Examples 1-5 and Comparative Example 1.

[0030] Figure 2 The microcrystal grid morphology diagram of the oil gel prepared by different BW contents of Examples 1-5 and Comparative Example 1.

[0031] Figure 3 The particle size change diagram of the lipid capsule during the air drying process prepared by different BW contents of Examples 1-5 and Comparative Example 1.

[0032] Figure 4 The capsule actual object diagram prepared by 5wt% BW content prepared by Example 3, fixed outer phase flow rate 300μL / min, and inner phase flow rate 15, 60, 105μL / min, respectively.

[0033] Figure 5 The SEM electron microscope diagram of the lipid capsule after air drying prepared by different inner phase production flow rates of Example 3 with 5wt% BW content.

[0034] Figure 6 The oil leakage comparison diagram of the lipid capsule with different BW contents at 25℃ and 50℃ in the temperature response experiment of Example 6.

[0035] Figure 7 The color change comparison diagram of the lipid capsule with different BW contents in the release process of coenzyme Q10 at 25℃ and 50℃ in the temperature response experiment of Example 6.

[0036] Figure 8Figure 1 shows the morphology of lipid capsules with different BW contents for the temperature response experiment of Example 6 at 25℃, t = 9h. From left to right, the BW contents are 0wt%, 1wt%, 5wt%, and 9wt%, respectively.

[0037] Figure 9 Figure 2 shows the morphology of lipid capsules with different BW contents for the temperature response experiment of Example 6 at 25℃, t = 9h. From left to right, the BW contents are 0wt%, 1wt%, 5wt%, and 9wt%, respectively. DETAILED DESCRIPTION

[0038] In order to make the above objectives, features and advantages of the present application more apparent, the specific embodiments of the present application will be described in detail below with reference to the embodiments of the present application.

[0039] In the following description, a large number of specific details are set forth in order to provide a thorough understanding of the present application. However, the present application can be practiced in other manners different from those described herein, and those skilled in the art can make similar generalizations without departing from the scope of the present application. Therefore, the specific embodiments disclosed below do not limit the present application.

[0040] Secondly, the "one embodiment" or "embodiment" referred to herein means that the specific features, structures or characteristics can be included in at least one implementation of the present application. The "in one embodiment" appearing in different places in the specification does not mean the same embodiment, nor is it an embodiment that is separate or alternative to other embodiments.

[0041] The sources of the raw materials in the embodiments of the present application are as follows: sodium alginate, Tween 80, and calcium chloride were purchased from the National Pharmaceutical Group Chemical Reagent Co., Ltd.; tropical plant oil palm kernel stearin extract (PKS) was provided by Yihai Kerry (Shanghai) Co., Ltd.; candelilla wax (CLW) was provided by Tianjin Wankeosi Co., Ltd.; beeswax (BW) was provided by Beijing Likang Weiye Technology Co., Ltd.; coenzyme Q10, β-carotene, and carvyl propionate were provided by Shanghai Aladdin Biochem Technology Co., Ltd.; camellia oil and other oils were purchased from a local supermarket (Wuxi, China). Other chemicals used herein were of analytical grade.

[0042] Example 1

[0043] (1) Accurately weigh 0.3g of BW, 0.3g of coenzyme Q10, and 29.4g of camellia oil into a clean and dry centrifuge tube to obtain a mixture. Place the centrifuge tube in a water bath at 80-85℃ to melt, and during the process, take out the centrifuge tube every certain period of time and shake on a vortex mixer to ensure that the prepared oil sample is uniform. Finally, wait until the BW is completely melted to obtain a camellia oil sample with a BW content of 1%, and cool the sample at room temperature to obtain an oil gel. 10 and 29.4g of camellia oil into a clean and dry centrifuge tube to obtain a mixture. Place the centrifuge tube in a water bath at 80-85℃ to melt, and during the process, take out the centrifuge tube every certain period of time and shake on a vortex mixer to ensure that the prepared oil sample is uniform. Finally, wait until the BW is completely melted to obtain a camellia oil sample with a BW content of 1%, and cool the sample at room temperature to obtain an oil gel.

[0044] (2) Accurately weigh 1 g of sodium alginate, 0.5 g of Tween-80 and 48.5 g of deionized water and pour into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture by a multi-point magnetic stirrer at room temperature (at a speed of 200-500 rpm / min for 2-4 h) until it is uniformly mixed, and obtain a sodium alginate solution after defoaming at room temperature.

[0045] (3) Accurately weigh 1.5 g of calcium chloride, 48.5 g of deionized water and pour into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture by a multi-point magnetic stirrer at room temperature (at a speed of 200-500 rpm / min for 1-2 min) until it is uniformly mixed, as a cross-linking liquid.

[0046] (4) The oil sample is heated and melted as an internal fluid, and the sodium alginate gel is used as an external fluid, and the O / W droplets are prepared by a coaxial co-extrusion microfluidic device, and then the droplets are dropped into a 3wt% calcium chloride cross-linking liquid for cross-linking for 1 h, and further form a double-network fixed calcium alginate lipid capsule, wherein the BW content is 1wt%.

[0047] (5) The 1wt% BW lipid capsule is air-dried for later use in temperature response experiments.

[0048] The morphology of the 1wt% BW oil gel after cooling is shown in Figure 1 (2), and it can be seen that 1% of the oil gel has not effectively bound the camellia oil; Figure 2 (2) is a microcrystal grid morphology diagram of the oil gel sample with a BW of 1wt%, and it can be seen that the oil gel with 1wt% BW begins to form a crystalline network; Figure 3 (2) is a particle size change diagram during the air-drying of the 1wt% BW, and it can be seen that the particle size of the lipid capsule after air-drying is almost the same as the inner core size of the microspheres just after preparation.

[0049] Example 2

[0050] (1) Accurately weigh 0.9 g of BW, 0.3 g of coenzyme Q 10 and 28.8 g of camellia oil into a clean and dry centrifuge tube to obtain a mixture. Heat and melt the centrifuge tube in a water bath at 80-85°C, and take it out every certain period of time during the heating and melt to shake it on a vortex mixer to ensure that the prepared oil sample is uniform. Finally, after waiting for the complete melting of the BW, the camellia oil sample with a BW content of 3% is obtained, and the oil gel is obtained after cooling at room temperature.

[0051] (2) Accurately weigh 1 g of sodium alginate, 0.5 g of Tween-80 and 48.5 g of deionized water and pour into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture by a multi-point magnetic stirrer at room temperature (at a speed of 200-500 rpm / min for 2-4 h) until it is mixed uniformly, and obtain a sodium alginate solution after defoaming at room temperature.

[0052] (3) Accurately weigh 1.5 g of calcium chloride, 48.5 g of deionized water and pour into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture by a multi-point magnetic stirrer at room temperature (at a speed of 200-500 rpm / min for 1-2 min) until it is mixed uniformly, as a cross-linking liquid.

[0053] (4) The oil sample is heated and melted as an internal fluid, and the sodium alginate gel is used as an external fluid, and the O / W droplets are prepared by a coaxial co-extrusion microfluidic device, and then the droplets are dropped into a 3wt% calcium chloride cross-linking liquid for cross-linking for 1 h, and further form a double-network fixed calcium alginate lipid capsule, wherein the BW content is 3wt%.

[0054] (5) The 3wt% BW lipid capsule is air-dried for later use in temperature response experiments.

[0055] The morphology of the 3wt% BW oil gel after cooling is shown in Figure 1 (3), and it can be seen that 3% of the oil gel can fix the camellia oil network; Figure 2 (3) is a microcrystal grid morphology diagram of the oil gel sample with a BW of 3wt%, and it can be seen that the oil gel with 3wt% BW forms a denser crystalline network than the 1wt% BW oil gel; Figure 3 (3) is a diagram of the change in particle size of the 3wt% BW lipid capsule during air-drying, and it can be seen that the particle size of the air-dried lipid capsule is almost the same as the inner core size of the microspheres just after preparation.

[0056] Example 3

[0057] (1) Accurately weigh 1.5 g of BW, 0.3 g of coenzyme Q 10 and 28.2 g of camellia oil into a clean and dry centrifuge tube to obtain a mixture. Heat the centrifuge tube in a water bath at 80-85°C to melt, and take it out every certain period of time during the process and shake it on a vortex mixer to ensure that the prepared oil sample is uniform. Finally, after waiting for the BW to melt completely, the camellia oil oil sample with a BW content of 5% is obtained, and the oil gel is obtained after cooling at room temperature.

[0058] (2) Accurately weigh 1 g of sodium alginate, 0.5 g of Tween-80 and 48.5 g of deionized water and pour into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture by a multi-point magnetic stirrer at room temperature (at a speed of 200-500 rpm / min for 2-4 h) until homogeneous, and obtain a sodium alginate solution after defoaming at room temperature.

[0059] (3) Accurately weigh 1.5 g of calcium chloride, 48.5 g of deionized water and pour into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture by a multi-point magnetic stirrer at room temperature (at a speed of 200-500 rpm / min for 1-2 min) until homogeneous, as a cross-linking liquid.

[0060] (4) The oil sample is heated and melted as an internal fluid, and the sodium alginate gel is used as an external fluid, and the O / W droplets are prepared by a coaxial co-extrusion microfluidic device, and are dropped into a 3wt% calcium chloride cross-linking liquid for cross-linking for 1 h, and further form a double-network fixed calcium alginate lipid capsule, wherein the BW content is 5wt%.

[0061] (5) The 5wt% BW lipid capsule is air-dried for subsequent temperature response experiments.

[0062] The morphology of the 5wt% BW oil gel after cooling is shown in Figure 1 (4) It can be seen that the 5% oil gel well immobilizes the camellia oil network; Figure 2 (4) is the microcrystal grid morphology diagram of the oil gel sample with a BW of 5wt%, and it can be seen that the oil gel with 5wt% BW forms a denser and more uniform crystalline network than the 3wt% BW oil gel; Figure 3 (4) is the particle size change diagram of the 5wt% BW lipid capsule during air-drying, and it can be seen that the particle size of the air-dried lipid capsule is almost the same as the inner core size of the microsphere just prepared.

[0063] Figure 4 The real object diagram of the capsule with a fixed outer phase flow rate and an inner phase flow rate increasing in turn just after preparation is shown in (4) at a BW of 5wt%, and it can be seen that as the inner phase flow rate increases, the inner core size increases and the shell becomes thinner.

[0064] Figure 5 The SEM electron microscope diagram of the 5wt% BW lipid capsule after air-drying is shown in (4) with different inner phase flow rates, and it can be seen that the larger the inner phase flow rate, the thinner the shell of the lipid capsule.

[0065] Example 4

[0066] (1) Accurately weigh 2.1 g of BW, 0.3 g of coenzyme Q 1027.6g of camellia oil was poured into a clean and dry centrifuge tube to obtain a mixture. The centrifuge tube was placed in a water bath at 80-85℃ and heated to melt. During this process, the centrifuge tube was removed periodically and shaken on a vortex mixer to ensure that the prepared oil sample was homogeneous. Finally, after the BW was completely melted, a camellia oil sample with a BW content of 7% was obtained. The sample was then cooled at room temperature to obtain an oil gel.

[0067] (2) Accurately weigh 1g of sodium alginate, 0.5g of Tween-80 and 48.5g of deionized water and pour them into a clean and dry glass container to obtain a mixture. Add a rotor and stir the mixture at room temperature using a multi-point magnetic stirrer (200-500 rpm / min for 2-4 hours) until it is uniformly mixed. After defoaming at room temperature, a sodium alginate solution is obtained.

[0068] (3) Accurately weigh 1.5g of calcium chloride and 48.5g of deionized water and pour them into a clean and dry glass container to obtain a mixture. Add a rotor and stir the mixture at room temperature using a multi-point magnetic stirrer (200-500 rpm / min for 1-2 min) until it is uniformly mixed, and use it as a crosslinking solution.

[0069] (4) The oil sample was heated and melted to serve as the internal fluid, and the sodium alginate gel was used as the external fluid. O / W droplets were prepared by coaxial co-extrusion microfluidic device and dropped into 3wt% calcium chloride crosslinking solution for 1h to further form a double network to fix calcium alginate lipid capsules, wherein the BW content was 7wt%.

[0070] (5) Air-dry the 7% BW lipid capsules for use in subsequent temperature response experiments.

[0071] The morphology of 7 wtw% BW olegel after cooling is as follows: Figure 1 As shown in (5), it can be seen that 7wt% oleogel effectively immobilizes the camellia oil network; Figure 2 (5) is a microscopic crystal network morphology diagram of oleogel with 7wt% BW. It can be seen that the oleogel with 7wt% BW added forms a denser and more uniform crystal network than the oleogel with 5wt% BW. Figure 3 (5) is a graph showing the particle size change of 7wt% BW lipid capsules during the air-drying process. It can be seen that the particle size of the lipid capsules after air-drying is almost the same as the core size of the microspheres when they were just prepared.

[0072] Example 5

[0073] (1) Accurately weigh 2.7g BW and 0.3g Coenzyme Q. 10and 27.0 g of camellia oil into a clean and dry centrifuge tube to obtain a mixture. The centrifuge tube was heated to melt in a water bath at 80-85℃, during which the centrifuge tube was taken out every time interval and shaken on a vortex mixer to ensure that the prepared oil sample was uniform. Finally, after waiting for the BW to melt completely, the oil sample with a BW content of 9% was obtained, and the oil gel was obtained after cooling at room temperature.

[0074] (2) Accurately weigh 1 g of sodium alginate, 0.5 g of Tween-80 and 48.5 g of deionized water and pour them into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture by a multi-point magnetic stirrer at room temperature (at a speed of 200-500 rpm / min for 2-4 h) until the mixture is uniform, and then defoam at room temperature to obtain a sodium alginate solution.

[0075] (3) Accurately weigh 1.5 g of calcium chloride, 48.5 g of deionized water and pour them into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture by a multi-point magnetic stirrer at room temperature (at a speed of 200-500 rpm / min for 1-2 min) until the mixture is uniform, and then defoam at room temperature to obtain a cross-linking solution.

[0076] (4) The oil sample was heated to melt as the internal fluid, and the sodium alginate gel was used as the external fluid. The O / W droplets were prepared by a coaxial co-extrusion microfluidic device, and were dropped into a 3wt% calcium chloride cross-linking solution for cross-linking for 1 h, and further formed a double-network fixed calcium alginate lipid capsule, wherein the BW content was 9wt%.

[0077] (5) The 9wt% BW lipid capsule was air-dried for subsequent temperature response experiments.

[0078] The morphology of the oil gel after cooling of the 9wt% BW is shown in Figure 1 (6), which shows that the 9wt% oil gel well immobilizes the camellia oil network; Figure 2 (6) is a microcrystal grid morphology diagram of the oil gel sample with a BW of 9wt%, which shows that the oil gel with 9wt% BW forms a more compact and uniform crystalline network than the 7wt% BW oil gel; Figure 3 (6) is a particle size change diagram during the air-drying process of the 9wt% BW, which shows that the particle size of the lipid capsule after air-drying is almost the same as the inner core size of the microsphere just after preparation.

[0079] As can be seen from Examples 1-5, a BW of 3wt% and above can form an oil gel with better binding capacity for liquid oil, therefore, the BW content is preferably ≥3wt%, wherein wt% is the mass ratio of the internal fluid.

[0080] Comparative Example 1

[0081] (1) Accurately weigh 0.3 g coenzyme Q 10 and 29.7 g camellia oil into a clean and dry centrifuge tube to obtain a mixture. Heat the centrifuge tube to melt in a water bath at 80-85 °C, and during the process, take out the centrifuge tube every certain time and shake on a vortex mixer to ensure that the prepared oil sample is uniform. Obtain the BW-free camellia oil sample, which is cooled at room temperature.

[0082] (2) Accurately weigh 1 g sodium alginate, 0.5 g Tween-80 and 48.5 g deionized water into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture by a multipoint magnetic stirrer at room temperature (at a speed of 200-500 rpm / min for 2-4 h) until the mixture is uniform, and obtain a sodium alginate solution after defoaming at room temperature.

[0083] (3) Accurately weigh 1.5 g calcium chloride and 48.5 g deionized water into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture by a multipoint magnetic stirrer at room temperature (at a speed of 200-500 rpm / min for 1-2 min) until the mixture is uniform, as a cross-linking liquid.

[0084] (4) The oil sample is heated to melt as an internal fluid, and the sodium alginate gel is used as an external fluid, and the O / W droplets are prepared by a coaxial co-extrusion microfluidic device, which are dropped into a 3 wt% calcium chloride cross-linking liquid for cross-linking for 1 h, and further form a double-network fixed calcium alginate lipid capsule.

[0085] (5) The BW-free lipid capsule is air-dried for subsequent temperature response experiments.

[0086] The morphology of the oil sample after cooling without BW is as shown in Figure 1 (1); Figure 2 (1) is a microcrystal grid morphology diagram of the oil gel sample without BW, and it can be seen that there is no crystal structure without BW; Figure 3 (1) is a particle size change diagram during the air-drying process of the 0% BW, and it can be seen that the particle size of the lipid capsule after air-drying is almost the same as the inner core size of the microsphere just after preparation.

[0087] It can be seen from Examples 1-5 and Comparative Example 1 that the addition of BW is important for the preparation of ultra-thin shell lipid capsules, and the addition of BW content of ≥3 wt% in the oil core can form a lipid crystal network to efficiently and stably fix the oil, and successfully construct a double-network encapsulation carrier.

[0088] Example 6

[0089] Temperature response experiment:

[0090] The prepared lipid capsules were air-dried, and two lipid capsules of each BW content were taken, and divided into A / B two groups, and one lipid capsule of each BW content was taken in each group. The A group was placed at room temperature (25℃) for 1h, and the B group was placed in a 50℃ oven for 1h. 30ml of isopropyl alcohol was taken in a beaker using a 5ml pipette, and then 1000μL of isopropyl alcohol solution was taken from the beaker into a 12 deep-well plate using a pipette. Each well contained 2ml of isopropyl alcohol solution. The silicone cover was labeled as 0A / 0B / 0C, 1A / 1B / 1C, 5A / 5B / 5C, 9A / 9B / 9C, respectively. One lipid capsule with coenzyme Q10 added was placed in each corresponding well, with the BW content being 0wt%, 1wt%, 5wt%, and 9wt%, respectively, and three parallel groups were prepared for each BW content. The plate was placed in a constant temperature incubator shaker, and the temperature was adjusted to 25℃ or 50℃ (the release experiment was carried out at two temperatures, respectively), and the plate was taken out every hour to observe the morphology of the lipid capsules.

[0091] The comparison chart of oil leakage of lipid capsules with different BW contents at 25℃ and 50℃ in the temperature response experiment is shown in Figure 6 It can be seen that when the temperature is higher than the melting point of BW, the oil leakage is obvious; but the higher the BW content, the less the oil leakage after 1h.

[0092] The comparison chart of color change of lipid capsules with different BW contents in the release process of coenzyme Q 10 at 25℃ and 50℃ is shown in Figure 7 It can be seen that when t=3h, the higher the temperature, the lighter the color of the lipid capsules, indicating that it has temperature response.

[0093] The morphology chart of lipid capsules with different BW contents at 25℃ and t=9h is shown in Figure 8 It can be seen that when t=9h and T=25℃, the morphology of lipid capsules with different BW contents is shown. Among them, the 0wt% BW lipid capsules are the whitest, the 1wt% BW is relatively white, the 5wt% BW is relatively yellow, and the 9wt% BW is the yellowest, indicating that the higher the BW content, the slower the release rate of coenzyme Q 10 , that is, the higher the BW content, the more obvious the sustained-release effect.

[0094] Comparative Example 2

[0095] (1) Accurately weigh 2.7g of BW, 0.3g of coenzyme Q 10 , and 27.0g of camellia oil into a clean and dry centrifuge tube to obtain a mixture. Place the centrifuge tube in a water bath at 80-85℃ to melt, and take it out every hour during the period and shake it on a vortex mixer to ensure that the prepared oil sample is uniform. Finally, wait until the BW is completely melted to obtain a camellia oil sample with a BW content of 9%, and cool it at room temperature to obtain an oil gel.

[0096] (2) Accurately weigh 1.5 g of sodium alginate, 0.5 g of Tween-80 and 48 g of deionized water and pour into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture by a multi-point magnetic stirrer at room temperature (at a speed of 200-500 rpm / min for 2-4 h) until it is uniformly mixed, and obtain a sodium alginate solution after defoaming at room temperature.

[0097] (3) Accurately weigh 1.5 g of calcium chloride, 48.5 g of deionized water and pour into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture by a multi-point magnetic stirrer at room temperature (at a speed of 200-500 rpm / min for 1-2 min) until it is uniformly mixed, as a cross-linking liquid.

[0098] (4) The oil sample is heated and melted as an internal fluid, and the sodium alginate gel is used as an external fluid, and the O / W droplets are prepared by a coaxial co-extrusion microfluidic device, and then the droplets are dropped into a 3 wt% calcium chloride cross-linking liquid for cross-linking for 1 h, and further form a double-network fixed calcium alginate lipid capsule, wherein the BW content is 9 wt%.

[0099] The difference between the present example and Example 5 is that the addition amount of sodium alginate is 3 wt%, which exceeds 2.5 wt%. Because the viscosity of the biological macromolecule is large, the sphericity of the prepared capsule is low, and there is a tailing phenomenon.

[0100] Comparative Example 3

[0101] (1) Accurately weigh 2.7 g of BW, 0.3 g of coenzyme Q 10 and 27.0 g of camellia oil into a clean and dry centrifuge tube to obtain a mixture. The centrifuge tube is placed in a water bath at 80-85°C for heating and melting, and during the process, the centrifuge tube is taken out at intervals and shaken on a vortex mixer to ensure that the prepared oil sample is uniform. Finally, after waiting for the BW to completely melt, the camellia oil sample with a BW content of 9% is obtained, and the oil gel is obtained after cooling at room temperature.

[0102] (2) Accurately weigh 1 g of sodium alginate, 0.125 g of Tween-80 and 48.875 g of deionized water and pour into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture by a multi-point magnetic stirrer at room temperature (at a speed of 200-500 rpm / min for 2-4 h) until it is uniformly mixed, and obtain a sodium alginate solution after defoaming at room temperature.

[0103] (3) Accurately weigh 1.5 g of calcium chloride and 48.5 g of deionized water and pour into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture at room temperature by a multi-point magnetic stirrer (at a speed of 200-500 rpm / min for 1-2 min) until it is uniformly mixed, as a cross-linking solution.

[0104] (4) The oil sample is heated and melted as the internal fluid, and the sodium alginate gel is used as the external fluid. The O / W droplets are prepared by a coaxial co-extrusion microfluidic device, and then dropped into the 3 wt% calcium chloride cross-linking solution for cross-linking for 1 h, to further form the double-network immobilized calcium alginate lipid capsules, wherein the BW content is 9 wt%.

[0105] The difference between the present example and Example 5 is that the amount of Tween-80 added is different. Since the amount of emulsifier added is low, it cannot play an emulsifying role, and the capsules with obvious single-core structure cannot be prepared, and the core-shell structure has obvious boundaries.

[0106] Comparative Example 4

[0107] (1) Accurately weigh 2.7 g of BW, 0.3 g of coenzyme Q 10 and 27.0 g of camellia oil into a clean and dry centrifuge tube to obtain a mixture. The centrifuge tube is placed in a water bath at 80-85°C for heating and melting. During the process, the centrifuge tube is taken out every certain period of time and shaken on a vortex mixer to ensure that the prepared oil sample is uniform. Finally, after waiting for the BW to completely melt, the camellia oil sample with a BW content of 9% is obtained, and the oil gel is obtained after cooling at room temperature.

[0108] (2) Accurately weigh 1 g of sodium alginate, 0.5 g of Tween-80 and 48.5 g of deionized water and pour into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture at room temperature by a multi-point magnetic stirrer (at a speed of 200-500 rpm / min for 2-4 h) until it is uniformly mixed, and then defoam at room temperature to obtain a sodium alginate solution.

[0109] (3) Accurately weigh 1.5 g of calcium chloride and 48.5 g of deionized water and pour into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture at room temperature by a multi-point magnetic stirrer (at a speed of 200-500 rpm / min for 1-2 min) until it is uniformly mixed, as a cross-linking solution.

[0110] (4) The oil sample is heated and melted as the internal fluid, and the sodium alginate gel is used as the external fluid. The O / W droplets are prepared by a coaxial co-extrusion microfluidic device, and then dropped into the 6 wt% calcium chloride cross-linking solution for cross-linking for 1 h, to further form the double-network immobilized calcium alginate lipid capsules, wherein the BW content is 9 wt%.

[0111] The comparative example is different from example 5 in that the amount of calcium chloride added is different. Due to the excessive amount of calcium chloride added, the sphericity of the capsule is affected.

[0112] Example 7

[0113] General verification of high-melting-point lipids and fat-soluble active substances:

[0114] (1) Accurately weigh 15 g of PKS, 0.3 g of carotene, and 14.7 g of camellia oil into a clean and dry centrifuge tube to obtain a mixture. Place the centrifuge tube in a water bath at 80-85°C to melt, and during the process, take out the centrifuge tube every hour and shake it on a vortex mixer to ensure that the prepared oil sample is uniform. Finally, wait until the PKS is completely melted to obtain a camellia oil sample with a PKS content of 50%, and cool it at room temperature to obtain an oil gel.

[0115] (2) Accurately weigh 1 g of sodium alginate, 0.5 g of Tween-80, and 48.5 g of deionized water into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture at room temperature by a multipoint magnetic stirrer (at a speed of 200-500 rpm / min for 2-4 h) until it is uniformly mixed, and then defoam at room temperature to obtain a sodium alginate solution.

[0116] (3) Accurately weigh 1.5 g of calcium chloride and 48.5 g of deionized water into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture at room temperature by a multipoint magnetic stirrer (at a speed of 200-500 rpm / min for 1-2 min) until it is uniformly mixed, as a crosslinking liquid.

[0117] (4) The oil sample is heated and melted as an internal fluid, and the sodium alginate gel is used as an external fluid. An O / W droplet is prepared by a coaxial co-extrusion microfluidic device, and is dropped into a 3 wt% calcium chloride crosslinking liquid for crosslinking for 1 h, to further form a double-network calcium alginate lipid capsule with a PKS content of 50 wt%.

[0118] (5) Air-dry the 50 wt% PKS lipid capsule.

[0119] The 50 wt% PKS lipid capsule is as shown in the first row, which proves that as long as the critical gel concentration of the gel factor is found, an amount greater than the critical gel concentration can be added to successfully construct an oil gel, and further prepare a lipid capsule; and the carotene is successfully encapsulated. Figure 9

[0120] Example 8

[0121] General verification of high-melting-point lipids and fat-soluble active substances:

[0122] ​(1) Accurately weigh 3 g of CLW, 0.3 g of carvacol and 26.7 g of camellia oil into a clean and dry centrifuge tube to obtain a mixture. Place the centrifuge tube in a water bath at 80-85 °C to melt, during which the centrifuge tube is taken out at intervals and shaken on a vortex mixer to ensure that the prepared oil sample is uniform. Finally, after waiting for the CLW to melt completely, a camellia oil sample with a CLW content of 10% is obtained, which is cooled at room temperature to obtain an oil gel.

[0123] (2) Accurately weigh 1 g of sodium alginate, 0.5 g of Tween-80 and 48.5 g of deionized water into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture at room temperature by a multipoint magnetic stirrer (at a speed of 200-500 rpm / min for 2-4 h) until it is uniformly mixed, and then defoam at room temperature to obtain a sodium alginate solution.

[0124] (3) Accurately weigh 1.5 g of calcium chloride and 48.5 g of deionized water into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture at room temperature by a multipoint magnetic stirrer (at a speed of 200-500 rpm / min for 1-2 min) until it is uniformly mixed, as a cross-linking liquid.

[0125] (4) The oil sample is heated and melted as an internal fluid, and the sodium alginate gel is used as an external fluid, and an O / W droplet is prepared by a coaxial co-extrusion microfluidic device, which is dropped into a 3 wt% calcium chloride cross-linking liquid for cross-linking for 1 h, and further forms a double-network calcium alginate lipid capsule with a CLW content of 10 wt%.

[0126] (5) The 10 wt% CLW lipid capsule is air-dried.

[0127] The 10 wt% CLW lipid capsule is air-dried. Figure 9 The second row shows that the universality of the application is verified again, and the CLW is successfully introduced to prepare a lipid capsule and successfully encapsulate carvacol.

[0128] Example 9

[0129] Precise quantification of fat-soluble active substances:

[0130] (1) Accurately weigh 2.7 g of BW, 0.3 g of coenzyme Q 10 and 27.0 g of camellia oil into a clean and dry centrifuge tube to obtain a mixture. Place the centrifuge tube in a water bath at 80-85 °C to melt, during which the centrifuge tube is taken out at intervals and shaken on a vortex mixer to ensure that the prepared oil sample is uniform. Finally, after waiting for the BW to melt completely, a camellia oil sample with a BW content of 9 wt% is obtained, which is cooled at room temperature to obtain an oil gel.

[0131] (2) Accurately weigh 1 g of sodium alginate, 0.5 g of Tween-80 and 48.5 g of deionized water and pour into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture by a multi-point magnetic stirrer at room temperature (at a speed of 200-500 rpm / min for 2-4 h) until uniform, and obtain a sodium alginate solution after defoaming at room temperature.

[0132] (3) Accurately weigh 1.5 g of calcium chloride, 48.5 g of deionized water and pour into a clean and dry glass container to obtain a mixture. Add a rotor, and stir the mixture by a multi-point magnetic stirrer at room temperature (at a speed of 200-500 rpm / min for 1-2 min) until uniform, as a cross-linking liquid.

[0133] (4) The oil sample is heated and melted as an internal fluid, and the sodium alginate gel is used as an external fluid. The external flow rate is adjusted to 300 μL / min, and the internal flow rate is 60 μL / min. The O / W droplets are prepared by a coaxial co-extrusion microfluidic device, dropped into a 3wt% calcium chloride cross-linking liquid for 1 min, cross-linked for 1 h, and further formed into a double-network fixed calcium alginate lipid capsule, wherein the BW content is 9wt%.

[0134] It can be obtained from the preparation time and the number of capsules produced that each capsule contains about 0.05 μL of coenzyme Q 10 The present application can realize the content control of fat-soluble active substances by adjusting the flow rate and controlling the amount of addition.

[0135] In summary, the more the BW content, the more the dense lipid gel network. The present application prepares the lipid capsule by a coaxial co-extrusion microfluidic device, which performs secondary wrapping on the oil and fat, improves the biocompatibility of the capsule, further improves the sustained-release performance of the liquid oil, and the ultra-thin shell lipid capsule prepared by the method has temperature response. The strategy has universality and is widely applicable to solid lipids. By introducing a crystallization factor, the liquid oil is bound to form a crystalline network to protect the fat-soluble active substances.

[0136] The present application is inspired by the structure of an egg, and a kind of lipid capsule with temperature intelligent response is prepared by wrapping gel oil with ultra-thin hydrogel shell. A high-melting-point lipid with strong gel ability is dispersed into liquid vegetable oil to form an oil gel with a dense network. Due to the introduction of high-melting-point lipids with melting temperature Tm, the lipid capsule has temperature response: below Tm, the oil gel is in a solid state; and above Tm, it melts into a liquid, allowing the release of the core content.

[0137] In the method of the present application, first, by introducing high melting point lipids, the liquid vegetable oil is captured in a three-dimensional network by crystallization, providing the first layer of protection for fat-soluble active substances. This process forms a lipid core with a three-dimensional network structure that responds to temperature; further, by upgrading the coaxial co-extrusion microfluidic device to form oil-in-water droplets, the water phase is introduced into natural polysaccharides such as sodium alginate, and then dropped into a calcium chloride solution to form a calcium alginate shell through calcium ion cross-linking. The gel oil is then wrapped in a second layer to form a capsule structure with a hydrogel shell and a gel oil core. After simple air drying, a lipid capsule with an ultra-thin shell is obtained.

[0138] The present application can precisely control the overall size and core size of the capsule by adjusting the flow rate of the water phase and the oil phase, and can give it precise quantitative function. In addition, the present application can achieve 100% active embedding rate, and has great application value in the fields of functional food and personal care, such as wrapping bacteriostatic ingredients, making bacteriostatic sachets, mask burst incense beads, etc.

[0139] It should be noted that the above examples are only used to illustrate the technical solutions of the present application and are not limiting. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the spirit and scope of the present application, and they should be included in the scope of the present application.

Claims

1. A method for preparing a temperature-responsive ultrathin lipid capsule, characterized in that: include, High-melting-point lipids were dissolved in liquid vegetable oil, fat-soluble active ingredients were added, and the mixture was heated to melt. After cooling at room temperature, an oleogel sample was obtained, which was an internal fluid. The heating temperature was 80~85℃. Sodium alginate and emulsifier were added to deionized water and stirred at room temperature to dissolve, resulting in an external fluid. An internal fluid and an external fluid are injected into a coaxial co-extrusion microfluidic device, the flow rate is set, and the internal fluid is heated to form O / W droplets. O / W droplets are dropped into calcium chloride solution at a certain height to crosslink, thus obtaining a lipid capsule with a temperature-responsive ultrathin shell. The process involves adding sodium alginate and an emulsifier to deionized water, wherein the emulsifier is at least one of Tween and sucrose ester; the mass ratio of sodium alginate, emulsifier, and deionized water is 1~2.5:0.5~2:

97. The set flow rate is as follows: the external phase flow rate is 100~300μL / min, and the internal phase flow rate is 15~120μL / min; The high-melting-point lipids are one or more of the following: rice bran wax (RBW), sunflower seed wax (SFW), candelilla wax (CLW), carnauba wax (CW), beeswax (BW), palm kernel oil (PKO), palm kernel stearin extract (PKS), coconut oil (CNO), and palm oil (PO). The calcium chloride solution has a mass of 1-5 wt%, where wt% is the weight percentage of the total weight of the solution.

2. The preparation method according to claim 1, characterized in that: The high-melting-point lipid is dissolved in a liquid vegetable oil, wherein the liquid vegetable oil is one or more of camellia oil, olive oil, peanut oil, sunflower seed oil, rapeseed oil, flaxseed oil, fish oil, and corn oil.

3. The preparation method according to claim 1, characterized in that: The addition of fat-soluble active ingredients includes EPA, DHA, β-carotene, astaxanthin, resveratrol, carvacrol, vitamin A, vitamin E, and coenzyme Q. 10 One or more of them.

4. The preparation method according to claim 1, characterized in that: The mass ratio of the high-melting-point lipid plus liquid vegetable oil to the fat-soluble active ingredient is 99:1 to 97:

3.

5. The preparation method according to claim 1, characterized in that: The O / W droplets are dropped into a calcium chloride solution at a certain height for cross-linking. The calcium chloride solution needs to be heated with a heating pad at a voltage of 120~130V. The height is 8~12cm and the cross-linking time is 0.5~2h.

6. A temperature-responsive ultrathin shell lipid capsule prepared by any one of the preparation methods described in claims 1 to 5.

7. The use of the lipid capsules as described in claim 6 in the preparation of functional foods and personal care products.

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