Capsule-in-capsule type gel bead as well as preparation method and application thereof

Abstract

The invention relates to a capsule-in-capsule type gel bead as well as a preparation method and application thereof. The capsule-in-capsule type gel bead comprises a water-in-oil type Pickering emulsion loaded with a water-soluble active matter and a calcium alginate gel layer wrapping the Pickering emulsion, the water-in-oil Pickering emulsion comprises a cured internal water phase, an oil phase and a solid particle emulsifier, the solidified inner water phase is prepared from the following raw materials: a water-soluble active matter, alginate, low-dissociation-degree calcium salt and water. According to the invention, the inner water phase of the Pickering emulsion is creatively cured as the inner capsule, so that the problem that the Pickering emulsion is unstable in freeze thawing, transportation and storage is solved; the combined protection of the particle interfacial film of the Pickering emulsion and the calcium alginate double-wall layer can isolate the influence of oxygen, illumination and water environment on the active matter, prevent environmental stress degradation, and achieve the purpose of improving the stability of the water-soluble active matter.

Description

Technical Field

[0001] The invention belongs to the technical field of cosmetics, and particularly relates to capsule-in-capsule type condensed beads and a preparation method and application thereof. Background Art

[0002] Functional bioactive substances are widely used in various fields, but there are still many unsatisfactory aspects in the field of cosmetics, which greatly reduce the effectiveness of active substances. For example, some active substances have low bioavailability and can only stay on the surface of the skin; in addition, active substances have poor stability, are sensitive to changes in the physical environment, and are easily inactivated, so they cannot remain stable for a long time.

[0003] Emulsification technology is a common method for encapsulating active ingredients in the cosmetics field. It can effectively improve the stability and bioavailability of active ingredients. Compared with the toxic surfactants used in traditional emulsions, Pickering emulsions prepared by solid particle emulsifiers have the advantages of high safety, low toxicity, environmental friendliness, and high stability, and have become a research hotspot in this field. For example, Jiang Hang et al. used silica nanoparticles and zein to form hydrophobic microspheres to stabilize W / O type Pickering emulsions. The system can effectively encapsulate vitamin C and show good stability during storage (Jiang H, Hu X, Jiang W, et al. Water-in-Oil Pickering Emulsions Stabilized by Hydrophobized Protein Microspheres [J]. Langmuir: the ACS journal of surfaces and colloids, 2022, 38 (40): 12273-12280. DOI: 10.1021 / acs.langmuir.2c01904.). However, in practical applications, freezing is a very important step in the transportation and storage of products. As a two-phase system, the water phase in the emulsion is very likely to form sharp ice crystals after freezing, destroying the interface structure, making the emulsion very likely to undergo flocculation, aggregation, oil-water separation and other changes after thawing, resulting in leakage and loss of activity of active substances, reducing the quality of emulsion products.

[0004] Existing methods for improving the freeze-thaw stability of emulsions include controlling ice crystal growth, changing the interface structure, changing the shear conditions and the composition of the emulsion. For example, Zhu Xue-Feng et al. used soy protein nanoparticles to stabilize Pickering emulsions to improve their freeze-thaw stability. The protein particles protected the emulsion by increasing the gel strength of the aqueous phase and forming a thicker interfacial film. They also explored the effect of salt addition on the freeze-thaw stability of the emulsion (Zhu XF, Zhang N, Lin WF, et al. Freeze-thaw stability of pickering emulsions stabilized by soy and whey protein particles [J]. Food Hydrocolloids, 2017, 69: 173-184. DOI: 10.1016 / j.foodhyd.2017.02.001.). This method can effectively improve the freeze-thaw stability of oil-in-water emulsions and the stability of lipophilic actives, but cannot improve the freeze-thaw stability of water-in-oil emulsions. More importantly, compared with the significant progress made in the delivery systems of lipophilic bioactive substances, there are fewer effective systems for loading hydrophilic active substances. This is mainly because hydrophilic substances have a serious tendency to leak into the external aqueous phase, making it more difficult to improve their stability.

[0005] Therefore, it is of great significance and broad market prospects to develop a capsule-in-capsule gel bead that improves the stability of water-soluble active ingredients and explore strategies to improve the freeze-thaw and transportation storage stability of water-in-oil Pickering emulsions. Summary of the invention

[0006] In view of the deficiencies in the prior art, the object of the present invention is to provide a capsule-in-capsule type gel bead and a preparation method and application thereof.

[0007] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0008] In a first aspect, the present invention provides a capsule-in-capsule gel bead, wherein the capsule-in-capsule gel bead comprises a water-in-oil type Pickering emulsion loaded with a water-soluble active substance and a calcium alginate gel layer wrapped outside the Pickering emulsion;

[0009] The water-in-oil type Pickering emulsion comprises a solidified internal water phase, an oil phase and a solid particle emulsifier;

[0010] The raw materials for preparing the solidified internal water phase include water-soluble active substances, alginate, low dissociation degree calcium salt and water.

[0011] The present invention creatively solidifies the inner water phase of the Pickering emulsion as an inner capsule, which can effectively overcome the instability problem of the Pickering emulsion during freeze-thaw and transportation and storage, and wraps a calcium alginate gel layer as an outer capsule. The combined protection of the particle interface membrane of the Pickering emulsion and the calcium alginate double wall layer can isolate the influence of oxygen, light and water environment on the active substance, prevent environmental stress degradation, and achieve the purpose of improving the stability of water-soluble active substances. The capsule-in-capsule structure can also further improve the stability of the Pickering emulsion during freeze-thaw and transportation and storage. The capsule-in-capsule type gel beads provided by the present invention can be applied to the field of cosmetics, reduce the influence of the external environment on water-soluble active substances, and effectively improve the stability of water-soluble active substances.

[0012] Preferably, the alginate comprises sodium alginate and / or potassium alginate.

[0013] Preferably, the low dissociation degree calcium salt includes any one or a combination of at least two of EDTA calcium disodium, calcium carbonate, calcium sulfate or calcium phosphate. More preferably, EDTA calcium disodium is used.

[0014] The present invention creatively selects calcium disodium ethylenediaminetetraacetate as the calcium salt, which can prevent calcium dissociation from occurring during the process of preparing the inner water phase, thereby preventing a gel reaction with sodium alginate. The gel formed in this way is in a lump shape, and cannot subsequently form a Pickering emulsion and an inner capsule structure, and cannot be secondary encapsulated into a calcium alginate capsule to form a capsule-in-capsule structure. On the other hand, calcium disodium ethylenediaminetetraacetate powder is colorless and transparent when dissolved in a sodium alginate solution, which is conducive to the subsequent display of the appearance of the product.

[0015] Preferably, the mass ratio of alginate, low dissociation degree calcium salt and water is (0.1-1.5):(0.05-2.5):100, wherein (0.1-1.5) can be selected from 0.1, 0.2, 0.3, 0.5, 0.7, 0.9, 1, 1.2, 1.4, 1.5, etc., and (0.05-2.5) can be selected from 0.05, 0.1, 0.5, 0.7, 1, 1.5, 2, 2.5, etc. Other specific point values ​​within the above numerical range can be selected, and they will not be described one by one here.

[0016] The term "water-soluble active ingredient" as used herein refers to a 1 wt% aqueous solution of the active ingredient, which is a uniform clear aqueous solution or a uniform dispersion at 25°C.

[0017] The water-soluble active substances include vitamin C, anthocyanidins, niacinamide, panthenol, sodium hyaluronate, arbutin, glabridin, etc. The amount of water-soluble active substances added is related to the solubility and effective amount of the water-soluble active substances. When different water-soluble active substances are used, the amount of water-soluble active substances added is also different. When the water-soluble active substance is vitamin C, the ratio of the amount of water-soluble active substance added to water is 1.8-500μg / mL, for example, 1.8μg / mL, 10μg / mL, 30μg / mL, 50μg / mL, 70μg / mL, 90μg / mL, 100μg / mL, 200μg / mL, 300μg / mL, 400μg / mL, 500μg / mL, etc. Other specific point values ​​within this numerical range can be selected, and they will not be repeated here.

[0018] Preferably, the raw materials for preparing the oil phase include an oil solution and a triggering agent.

[0019] Preferably, the addition ratio of the trigger and the oil solution is (0.5-5) g:100 mL, for example, 0.5 g:100 mL, 0.7 g:100 mL, 0.9 g:100 mL, 1 g:100 mL, 1.5 g:100 mL, 2 g:100 mL, 2.5 g:100 mL, 3 g:100 mL, 3.5 g:100 mL, 4 g:100 mL, 4.5 g:100 mL, 5 g:100 mL, etc. Other specific point values ​​within this numerical range can be selected, and they will not be described one by one here.

[0020] Preferably, the oil solution comprises any one of caprylic / capric triglyceride, white oil or medium-chain fatty acid triglyceride, or a combination of at least two thereof.

[0021] Preferably, the trigger comprises a weak acid or a lactone.

[0022] Preferably, the weak acid comprises any one of glacial acetic acid, carbonic acid, citric acid or lactic acid, or a combination of at least two thereof, and more preferably glacial acetic acid.

[0023] Preferably, the lactone includes any one of D-glucono-δ-lactone, γ-butyrolactone, ε-caprolactone or δ-valerolactone, or a combination of at least two thereof.

[0024] Preferably, the solid particle emulsifier is a hydrophobic solid particle emulsifier.

[0025] Preferably, the hydrophobic solid particle emulsifier comprises hydrophobic silica.

[0026] Preferably, the addition ratio of the solid particle emulsifier to the oil phase is (0.1-1) g:10mL, for example 0.1g:10mL, 0.2g:10mL, 0.3g:10mL, 0.4g:10mL, 0.5g:10mL, 0.6g:10mL, 0.7g:10mL, 0.8g:10mL, 0.9g:10mL, 1g:10mL, other specific point values ​​within this numerical range can be selected, and they will not be described one by one here.

[0027] Preferably, the volume ratio of the oil phase to the solidified inner water phase in the water-in-oil type Pickering emulsion is 10:(1-16), for example, 10:1, 10:2, 10:3, 10:5, 10:7, 10:9, 10:10, 10:12, 10:14, 10:15, 10:16, etc. Other specific point values ​​within this numerical range can be selected and will not be described one by one here.

[0028] Preferably, the raw materials for preparing the calcium alginate gel layer include high dissociation degree calcium salt and alginate.

[0029] Preferably, the high dissociation degree calcium salt includes any one of calcium chloride, calcium bromide, calcium dihydrogen phosphate, calcium lactate or calcium gluconate, or a combination of at least two thereof.

[0030] Preferably, the alginate comprises sodium alginate and / or potassium alginate.

[0031] The encapsulation material selected in the present invention is sodium alginate, which is a safe and simple carrier that can react with Ca under mild conditions. 2+ Combined to form calcium alginate gel, the three-dimensional network structure of calcium alginate gel makes it widely used in active substance encapsulation, and the gel production conditions are not harsh and the production process is simple.

[0032] Preferably, the water-in-oil Pickering emulsion is prepared by the following method, which comprises:

[0033] (1) mixing alginate with water, dissolving it, adding a water-soluble active ingredient, dissolving it, adding calcium salt, and obtaining an inner water phase;

[0034] (2) dissolving a solid particle emulsifier in an oil solution, dispersing the solid particle emulsifier, and adding a triggering agent to obtain an oil phase;

[0035] (3) The oil phase and the inner water phase are mixed, emulsified, and allowed to stand until the emulsion layer is stable to obtain the water-in-oil type Pickering emulsion.

[0036] In a second aspect, the present invention provides a method for preparing the capsule-in-capsule type gel beads according to the first aspect, the preparation method comprising the following steps:

[0037] (1) using a water-in-oil type Pickering emulsion as the inner phase liquid; mixing alginate with water and dissolving them to obtain an alginate solution as the outer phase liquid; mixing a high dissociation degree calcium salt with water and dissolving them to obtain a high dissociation degree calcium salt solution as the receiving liquid;

[0038] (2) The external phase liquid shears the internal phase liquid to form droplets, which are then dropped into the receiving liquid and cross-linked to form calcium alginate beads;

[0039] (3) The calcium alginate beads are allowed to stand and solidify to obtain the capsule-in-capsule type beads.

[0040] Preferably, the mass fraction of alginate in the alginate solution of step (1) is 1.5-2.5%, for example 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, etc. Other specific point values ​​within this numerical range can be selected and will not be described here one by one.

[0041] Preferably, the mass fraction of the high dissociation degree calcium salt in the high dissociation degree calcium salt solution is 0.5-10%, for example 0.5%, 0.7%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8t%, 9%, 10%, etc. Other specific point values ​​within this numerical range can be selected and will not be described one by one here.

[0042] Preferably, the method of step (2) causing the external phase liquid to shear the internal phase liquid to form droplets comprises:

[0043] Use two injection pumps, the one connected to the inner phase liquid is the inner phase pump, and the one connected to the outer phase liquid is the outer phase pump; first turn on the switch of the inner phase pump, and close it after the inner phase liquid fills the dripper, then turn on the switch of the outer phase pump, and turn on the switch of the inner phase pump again after the outer phase liquid fills the dripper and completely wraps the inner phase liquid. The outer phase liquid shears the inner phase liquid at the dripper to form droplets.

[0044] Preferably, the inner diameter of the hose connected to the internal phase pump is 0.4-0.6mm (for example, 0.4mm, 0.5mm, 0.6mm, etc.), and the flow rate of the pump is 100-500μL / min (for example, 100μL / min, 200μL / min, 300μL / min, 400μL / min, 500μL / min, etc.); the inner diameter of the hose connected to the external phase pump is 0.9-1.1mm (for example, 0.9mm, 1mm, 1.1mm, etc.), and the pump flow rate is 700-1000μL / min (for example, 700μL / min, 800μL / min, 900μL / min, 1000μL / min, etc.), and other specific point values ​​within the above numerical range can be selected, which will not be repeated here.

[0045] In a third aspect, the capsule-in-capsule type gel beads described in the first aspect of the present invention are used in the preparation of cosmetics.

[0046] Compared with the prior art, the present invention has the following beneficial effects:

[0047] The present invention creatively solidifies the inner water phase of the Pickering emulsion as an inner capsule, which can effectively overcome the instability problem of the Pickering emulsion during freeze-thaw and transportation and storage, and wraps the calcium alginate gel as an outer capsule. The combined protection of the particle interface film of the Pickering emulsion and the calcium alginate double wall layer can isolate the influence of oxygen, light and water environment on the active substance, prevent environmental stress degradation, and achieve the purpose of improving the stability of water-soluble active substances. At the same time, the capsule-in-capsule structure can also further improve the stability of the Pickering emulsion during freeze-thaw and transportation and storage. The capsule-in-capsule type gel beads provided by the present invention can be applied to the field of cosmetics, reduce the influence of the external environment on water-soluble active substances, and effectively improve the stability of water-soluble active substances. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 The schematic diagram of the instillation for preparing capsule-in-capsule type gel beads;

[0049] Figure 2 This is a photo of capsule-in-capsule condensation beads prepared in Example 1 in a screw-mouth glass bottle;

[0050] Figure 3 This is a photo of the capsule-in-capsule condensation beads prepared in Example 1 at the bottom of a screw-mouth glass bottle;

[0051] Figure 4 This is a magnified photograph of the surface of a single capsule-in-capsule type gel bead prepared in Example 1;

[0052] Figure 5 This is a photo of a single capsule-in-capsule type gel bead prepared in Example 1, which contains small capsules loaded inside;

[0053] Figure 6 The morphology and size of the capsule-in-capsule type gel beads prepared in Example 1;

[0054] Figure 7 The schematic diagram of the structure of capsule-in-capsule type gel beads prepared in Example 1;

[0055] Figure 8 This is a scanning electron microscope image of the inner capsule in the capsule-in-capsule type gel beads prepared in Example 1;

[0056] Fig. 9 This is an enlarged view of the surface of the inner capsule in the capsule-in-capsule type gel beads prepared in Example 1;

[0057] Fig.10 This is a photo of the capsule-in-capsule gel beads just prepared in Example 1;

[0058] Fig.11 This is a photo of the capsule-in-capsule gel beads stored for 270 days in Example 1;

[0059] Fig.12 The microscope photo and macroscopic photo of the Pickering emulsion of Comparative Example 2 just prepared;

[0060] Fig.13 The microscope and macroscopic photographs of the Pickering emulsion of Comparative Example 2 after freeze-thaw cycles;

[0061] Fig.14 The microscope photo and macroscopic photo of the Pickering emulsion of Comparative Example 3 just prepared;

[0062] Fig.15 The microscope photo and macroscopic photo of the Pickering emulsion of Comparative Example 3 after freeze-thaw cycles;

[0063] Fig.16 This is a photo of the capsule-in-capsule gel beads just prepared in Example 1;

[0064] Fig.17 This is a photograph of the capsule-in-capsule gel beads of Example 1 after 120 days of oscillation in an oscillator to simulate the transport process. DETAILED DESCRIPTION

[0065] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0066] In the following examples, unless otherwise specified, the reagents and consumables used were purchased from conventional reagent manufacturers in the field; unless otherwise specified, the experimental methods and technical means used were conventional methods and means in the field.

[0067] The hydrophobic silica involved in the following examples was purchased from Shanghai MacLean Biochemical Technology Co., Ltd. as hydrophobic nano-silica (product number S861489).

[0068] Caprylic / capric triglyceride was purchased from Wilmar Oil & Fats Technology Co., Ltd. as an analytically pure product;

[0069] White oil was purchased from Shanghai Dike Fine Chemical Co., Ltd. Chemically pure products.

[0070] Example 1

[0071] This embodiment provides a capsule-in-capsule type gel beads, and the preparation method is as follows:

[0072] (1) Weigh 0.16 g of sodium alginate and dissolve it in 16 mL of deionized water, stir and dissolve it completely at 1000 r / min to obtain a sodium alginate solution with a mass fraction of 1%, then add 0.008 g of vitamin C, stir and dissolve it at 1000 r / min to obtain a sodium alginate solution dissolved with vitamin C;

[0073] (2) adding 0.032 g of calcium disodium ethylenediaminetetraacetate to obtain an inner aqueous phase in step (1);

[0074] (3) Weigh 0.8 g of hydrophobic silica and dissolve it in 20 mL of caprylic / capric triglyceride, and disperse it in a magnetic stirrer to make the hydrophobic silica particles completely dispersed in the oil solution;

[0075] (4) adding 0.525 g of glacial acetic acid to the solution obtained in step (3), and shaking the mixture in a vortex mixer to obtain an oil phase;

[0076] (5) After mixing 20 mL of the oil phase and 16 mL of the inner water phase, the mixture was shaken by hand for 2 minutes to form an emulsion, and the mixture was allowed to stand until the emulsion layer was stable, thereby obtaining a W / O type Pickering emulsion in which the inner water phase was solidified, which was used as the inner phase liquid;

[0077] (6) Weigh 2 g of sodium alginate and dissolve it in 100 mL of deionized water. Place the mixture in a heated magnetic stirrer and stir to dissolve at 50° C. at a speed of 1000 r / min to prepare a sodium alginate solution with a mass fraction of 2% as the external phase liquid;

[0078] (7) Weigh 2 g of calcium chloride and dissolve it in 100 mL of deionized water to prepare a 2% calcium chloride solution as a receiving solution;

[0079] (8) The inner phase liquid and the outer phase liquid were respectively drawn into 5 mL and 10 mL syringes and connected to two syringe pumps. The inner phase liquid was connected to the inner phase pump, and the inner diameter of the connected hose was 0.5 mm. The flow rate of the pump was 250 μL / min. The outer phase liquid was connected to the outer phase pump, and the inner diameter of the connected hose was 0.9 mm. The flow rate of the pump was 1000 μL / min. The switch of the inner phase pump was first turned on, and then turned off after the inner phase liquid filled the dripper. Then the switch of the outer phase pump was turned on again after the outer phase liquid filled the dripper and wrapped the inner phase liquid, so that the system of the outer phase liquid wrapping the inner phase liquid was dripped into the receiving liquid for cross-linking. The dripping process was as follows: Figure 1 As shown. After 2 hours of cross-linking reaction, the calcium alginate capsule was taken out. The capsule surface was washed with deionized water for 3 times. The washed spherical capsule was the capsule-in-capsule condensate bead.

[0080] The photo of the capsule-in-capsule condensation beads prepared in Example 1 in a screw-mouth glass bottle is shown in FIG. Figure 2 As shown, a photo of three capsule-in-capsule-shaped beads at the bottom of a screw-mouth glass bottle Figure 3As shown, the enlarged photo of the surface of a single condensate bead is shown Figure 4 As shown, the photo of the small capsule loaded inside a single bead is as follows Figure 5 shown.

[0081] Example 2

[0082] (1) Weigh 0.032 g of sodium alginate and dissolve it in 16 mL of deionized water, stir and dissolve it completely at 800 r / min to obtain a sodium alginate solution with a mass fraction of 0.2%, then add 0.006 g of vitamin C, stir and dissolve it at 800 r / min to obtain a sodium alginate solution dissolved with vitamin C;

[0083] (2) adding 0.009 g of calcium carbonate to obtain an inner aqueous phase in step (1);

[0084] (3) Weigh 0.6 g of hydrophobic silica and dissolve it in 20 mL of white oil, and disperse it in a magnetic stirrer to make the hydrophobic silica particles completely dispersed in the oil solution;

[0085] (4) adding 0.2 g of glacial acetic acid to the solution obtained in step (3), and shaking the mixture in a vortex mixer to obtain an oil phase;

[0086] (5) After mixing 20 mL of the oil phase and 12 mL of the inner water phase, the mixture was shaken by hand for 2 minutes to form an emulsion, and the mixture was allowed to stand until the emulsion layer was stable, thereby obtaining a W / O type Pickering emulsion with the inner water phase solidified as the inner phase liquid;

[0087] (6) Weigh 1.5 g of sodium alginate and dissolve it in 100 mL of deionized water. Place the mixture in a heated magnetic stirrer and stir at 50° C. to dissolve the mixture at a speed of 800 r / min to obtain a sodium alginate solution with a mass fraction of 1.5%, which serves as the external phase liquid.

[0088] (7) Weigh 1.5 g of calcium chloride and dissolve it in 100 mL of deionized water to prepare a 1.5% calcium chloride solution as a receiving solution;

[0089] (8) The inner phase liquid and the outer phase liquid were respectively drawn into 5 mL and 10 mL syringes and connected to two syringe pumps. The inner phase liquid was connected to the inner phase pump, the inner diameter of the connected hose was 0.5 mm, and the pump flow rate was 250 μL / min. The outer phase liquid was connected to the outer phase pump, the inner diameter of the connected hose was 0.9 mm, and the pump flow rate was 1000 μL / min. First, turn on the switch of the inner phase pump, wait for the inner phase liquid to fill the dripper, then turn it off, and then turn on the switch of the outer phase pump. After the outer phase liquid fills the dripper and wraps the inner phase liquid, turn on the switch of the inner phase pump again, so that the system of the outer phase liquid wrapping the inner phase liquid is dripped into the receiving liquid for crosslinking. After 2 hours of crosslinking reaction, take out the calcium alginate capsule. Wash the surface of the capsule with deionized water 3 times. The washed spherical capsule is the capsule-in-capsule capsule.

[0090] Example 3

[0091] (1) Weigh 0.24 g of sodium alginate and dissolve it in 16 mL of deionized water, stir and dissolve it completely at 1500 r / min to obtain a sodium alginate solution with a mass fraction of 1.5%, then add 0.005 g of vitamin C, stir and dissolve it at 1500 r / min to obtain a sodium alginate solution dissolved with vitamin C;

[0092] (2) adding 0.16 g of calcium disodium ethylenediaminetetraacetate to obtain an inner aqueous phase in step (1);

[0093] (3) Weigh 1 g of hydrophobic silica and dissolve it in 20 mL of caprylic / capric triglyceride, and disperse it in a magnetic stirrer to make the hydrophobic silica particles completely dispersed in the oil solution;

[0094] (4) adding 0.9 g of D-glucono-δ-lactone to the solution obtained in step (3), and shaking the mixture in a vortex mixer to obtain an oil phase;

[0095] (5) After mixing 10 mL of the oil phase and 12 mL of the inner water phase, the mixture was shaken by hand for 2 minutes to form an emulsion, and the mixture was allowed to stand until the emulsion layer was stable, thereby obtaining a W / O type Pickering emulsion with the inner water phase solidified as the inner phase liquid;

[0096] (6) Weigh 2.5 g of sodium alginate and dissolve it in 100 mL of deionized water. Place the mixture in a heated magnetic stirrer and stir it at 50° C. at a speed of 1500 r / min to prepare a sodium alginate solution with a mass fraction of 2.4% as the external phase liquid;

[0097] (7) Weigh 5 g of calcium chloride and dissolve it in 100 mL of deionized water to prepare a calcium chloride solution with a mass fraction of 4.8% as a receiving solution;

[0098] (8) The inner phase liquid and the outer phase liquid were respectively drawn into 5 mL and 10 mL syringes and connected to two syringe pumps. The inner phase liquid was connected to the inner phase pump, the inner diameter of the connected hose was 0.5 mm, and the pump flow rate was 250 μL / min. The outer phase liquid was connected to the outer phase pump, the inner diameter of the connected hose was 0.9 mm, and the pump flow rate was 1000 μL / min. First, turn on the switch of the inner phase pump, wait for the inner phase liquid to fill the dripper, then turn it off, and then turn on the switch of the outer phase pump. After the outer phase liquid fills the dripper and wraps the inner phase liquid, turn on the switch of the inner phase pump again, so that the system of the outer phase liquid wrapping the inner phase liquid is dripped into the receiving liquid for crosslinking. After 2 hours of crosslinking reaction, take out the calcium alginate capsule. Wash the surface of the capsule with deionized water 3 times. The washed spherical capsule is the capsule-in-capsule capsule.

[0099] Example 4

[0100] This embodiment provides a capsule-in-capsule type gel beads, which differ from Embodiment 1 only in that in step (2), 0.48 g of calcium disodium ethylenediaminetetraacetate is added to step (1) to obtain an inner water phase, and other conditions remain unchanged.

[0101] Example 5

[0102] This embodiment provides a capsule-in-capsule type gel beads, which differ from Embodiment 1 only in that in step (2), 0.005 g of calcium disodium ethylenediaminetetraacetate is added to step (1) to obtain an inner water phase, and other conditions remain unchanged.

[0103] Example 6

[0104] This embodiment provides a capsule-in-capsule gel beads, which differ from Embodiment 1 only in that in step (3), 2.5 g of hydrophobic silica is weighed and dissolved in 20 mL of caprylic / capric triglyceride, and other conditions remain unchanged.

[0105] Example 7

[0106] This embodiment provides a capsule-in-capsule gel beads, which differ from Embodiment 1 only in that step (3) 0.1 g of hydrophobic silica is weighed and dissolved in 20 mL of caprylic / capric triglyceride, and other conditions remain unchanged.

[0107] Example 8

[0108] This embodiment provides a capsule-in-capsule type gel beads, which differ from Embodiment 1 only in that in step (4), 1.5 g of glacial acetic acid is added to the solution obtained in step (3), and other conditions remain unchanged.

[0109] Example 9

[0110] This embodiment provides a capsule-in-capsule type gel beads, which differ from Embodiment 1 only in that in step (4), 0.05 g of glacial acetic acid is added to the solution obtained in step (3), and other conditions remain unchanged.

[0111] Example 10

[0112] The present embodiment provides a capsule-in-capsule type gel beads, which differ from the embodiment 1 only in that in step (5), 20 mL of oil phase and 1 mL of inner water phase are mixed, and emulsified by hand for 2 minutes to form an emulsion, and then allowed to stand until the emulsion layer is stable, thereby obtaining a W / O type Pickering emulsion with the inner water phase solidified as the inner phase liquid, and other conditions remain unchanged.

[0113] Embodiment 11

[0114] The present embodiment provides a capsule-in-capsule type gel beads, which differ from the embodiment 1 only in that in step (5), 5 mL of oil phase and 10 mL of inner water phase are mixed, and emulsified by hand for 2 minutes to form an emulsion, and then allowed to stand until the emulsion layer is stable, thereby obtaining a W / O type Pickering emulsion with the inner water phase solidified as the inner phase liquid, and other conditions remain unchanged.

[0115] Example 12

[0116] This embodiment provides a capsule-in-capsule type gel beads, which differ from Embodiment 1 only in that step (6) weighs 1 g of sodium alginate and dissolves it in 100 mL of deionized water, placing it in a heated magnetic stirrer and stirring it at 50° C. to prepare a sodium alginate solution with a mass fraction of 1% as the external phase liquid.

[0117] Example 13

[0118] This embodiment provides a capsule-in-capsule type gel beads, which differ from Embodiment 1 only in that step (6) weighs 3 g of sodium alginate and dissolves it in 100 mL of deionized water, placing it in a heated magnetic stirrer and stirring it at 50° C. to prepare a sodium alginate solution with a mass fraction of 3% as the external phase liquid.

[0119] Comparative Example 1

[0120] This embodiment provides a capsule-in-capsule type gel beads, and the preparation method is as follows:

[0121] (1) Weigh 0.008 g of vitamin C and dissolve it in 16 mL of deionized water, stirring at 1000 r / min to dissolve, to obtain an inner aqueous phase;

[0122] (2) weighing 0.8 g of hydrophobic silica and dissolving it in 20 mL of caprylic / capric triglyceride, and dispersing it in a magnetic stirrer so that the hydrophobic silica particles are completely dispersed in the oil solution to obtain an oil phase;

[0123] (3) After the oil phase and the inner water phase are mixed, they are manually shaken for 2 minutes to form an emulsion, and then allowed to stand until the emulsion layer is stable, thereby obtaining a W / O type Pickering emulsion as the inner phase liquid;

[0124] (4) Weigh 2 g of sodium alginate and dissolve it in 100 mL of deionized water. Place the mixture in a heated magnetic stirrer and stir to dissolve at 50° C. at a speed of 1000 r / min to prepare a sodium alginate solution with a mass fraction of 2% as the external phase liquid;

[0125] (5) Weigh 2 g of calcium chloride and dissolve it in 100 mL of deionized water to prepare a 2% calcium chloride solution as a receiving solution;

[0126] (6) The inner phase liquid and the outer phase liquid were respectively drawn into 5 mL and 10 mL syringes and connected to two syringe pumps. The inner phase liquid was connected to the inner phase pump, the inner diameter of the connected hose was 0.5 mm, and the pump flow rate was 250 μL / min. The outer phase liquid was connected to the outer phase pump, the inner diameter of the connected hose was 0.9 mm, and the pump flow rate was 1000 μL / min. First, turn on the switch of the inner phase pump, wait for the inner phase liquid to fill the dripper, then turn it off, and then turn on the switch of the outer phase pump. After the outer phase liquid fills the dripper and wraps the inner phase liquid, turn on the switch of the inner phase pump again, so that the system of the outer phase liquid wrapping the inner phase liquid is dripped into the receiving liquid for cross-linking. After 2 hours of cross-linking reaction, take out the calcium alginate capsule. Wash the capsule surface with deionized water 3 times. The washed spherical capsule is the capsule-in-capsule capsule.

[0127] Comparative Example 2

[0128] This embodiment provides a Pickering emulsion solidified in an internal water phase, and the preparation method is as follows:

[0129] (1) Weigh 0.16 g of sodium alginate and dissolve it in 16 mL of deionized water, stir and dissolve it completely at 1000 r / min to obtain a sodium alginate solution with a mass fraction of 1%, then add 0.008 g of vitamin C and stir and dissolve it at 1000 r / min to obtain a sodium alginate solution dissolved with vitamin C;

[0130] (2) adding 0.032 g of calcium disodium ethylenediaminetetraacetate to obtain an inner aqueous phase in step (1);

[0131] (3) Weigh 0.8 g of hydrophobic silica and dissolve it in 20 mL of caprylic / capric triglyceride, and disperse it in a magnetic stirrer to make the hydrophobic silica particles completely dispersed in the oil solution;

[0132] (4) adding 0.525 g of glacial acetic acid to the solution obtained in step (3), and shaking the mixture in a vortex mixer to obtain an oil phase;

[0133] (5) After the oil phase and the inner water phase are mixed, they are shaken by hand for 2 minutes to form an emulsion, and then allowed to stand until the emulsion layer is stable, thereby obtaining a W / O type Pickering emulsion with a solidified inner water phase.

[0134] Comparative Example 3

[0135] This embodiment provides a Pickering emulsion, and the preparation method is as follows:

[0136] (1) Weigh 0.008 g of vitamin C and dissolve it in 16 mL of deionized water, stirring at 1000 r / min to dissolve, to obtain an inner aqueous phase;

[0137] (2) weighing 0.8 g of hydrophobic silica and dissolving it in 20 mL of caprylic / capric triglyceride, and dispersing it in a magnetic stirrer so that the silica particles are completely dispersed in the oil solution to obtain an oil phase;

[0138] (3) After the oil phase and the inner water phase are mixed, they are shaken by hand for 2 minutes to form an emulsion. The mixture is allowed to stand until the emulsion layer is stable, thereby obtaining a W / O type Pickering emulsion.

[0139] Test Example 1

[0140] (1) After washing the capsule-in-capsule-shaped beads obtained in Example 1, the beads were placed in a watch glass and their morphology and size were observed. The results were as follows: Figure 6 As shown, the capsule-in-capsule-shaped beads prepared in Example 1 have good morphology and are spherical in shape, with a size of 3 mm.

[0141] (2) After washing away the moisture on the surface of the capsule-in-capsule-shaped condensed beads prepared in Example 1, the beads were frozen with liquid nitrogen, and subjected to gold spraying. The surface and cross-sectional morphologies of the capsule-in-capsule-shaped condensed beads were photographed using a scanning electron microscope. Figure 7 This is a schematic diagram of calcium alginate gel encapsulating Pickering emulsion (inner capsule), and the structure of the inner capsule is as follows Figure 8 As shown, the surface structure is further enlarged as Fig. 9 As shown, it can be seen that it is covered with silicon dioxide to form a silicon dioxide particle film.

[0142] Test Example 2

[0143] (1) Long-term storage stability: The capsule-in-capsule gel beads prepared in Example 1 were placed in water containing a preservative and stored for a long time. Fig.10 As shown in Figure 2, the beads were stored for 270 days at 25°C. Fig.11 As shown, it can be seen that the calcium alginate wall material is intact and the emulsion encapsulated inside does not break and leak, indicating that the capsule-in-capsule type gel beads prepared by the present invention have good long-term storage stability.

[0144] (2) Freeze-thaw stability:

[0145] The microscopic and macroscopic photos of the Pickering emulsion solidified in the water phase of the just prepared comparative example 2 (i.e., the inner capsule of the capsule-in-capsule type gel beads of Example 1) are shown in FIG. Fig.12 As shown, the microscopic and macroscopic photos after freezing at -24 °C for 24 h and thawing at room temperature for 3 h and thawing for 10 times are shown in Fig.13 As shown, it was observed that the particle size of the inner capsule remained basically unchanged, and the emulsified volume was about 75%;

[0146] Microscope photos and macroscopic photos of the Pickering emulsion of Comparative Example 3 just prepared are as follows: Fig.14As shown, the microscopic and macroscopic photos after freezing at -24 °C for 24 h and thawing at room temperature for 3 h and thawing for 10 times are shown in Fig.15 As shown, it was found that the particle size of the emulsion became larger and the emulsified volume was about 21%.

[0147] It can be concluded that the solidification of the inner aqueous phase gel can effectively improve the freeze-thaw stability of the Pickering emulsion.

[0148] (3) Transportation stability: The capsule-in-capsule gel beads of Example 1 were just prepared. Fig.16 As shown, it was placed in a screw bottle filled with deionized water and shaken in an oscillator to simulate the product transportation process. After 120 days, Fig.17 As shown, there is no obvious change in the appearance of the capsule, no swelling phenomenon occurs, and the encapsulated vitamin C does not leak, indicating that the capsule-in-capsule type gel bead encapsulation system prepared by the present invention has good transportation stability.

[0149] Test Example 3

[0150] Vitamin C retention rate determination:

[0151] The products prepared in Examples 1-13 and Comparative Examples 1-3 were stored at 25°C in a dark place for 27 days, and the absorbance of the product solution (the product was dispersed in a citric acid-sodium citrate buffer solution with a mass ratio of 1:5 at pH=5.2) at 256 nm was tested on the 3rd, 12th and 27th days, respectively, and the relative retention rate on the i-th day was calculated according to the following formula. A citric acid-sodium citrate buffer solution (pH=5.2) containing 0.5wt% vitamin C was used as the control group, and the results are shown in Table 1.

[0152] Relative retention rate (%) = (A i -A0) / (A j -A0)×100%

[0153] Among them, A i The absorbance on the i-th day of storage in the dark; A j is the absorbance on day 0; A0 is the absorbance of citric acid-sodium citrate buffer at pH = 5.2.

[0154] Table 1

[0155]

[0156]

[0157] It can be seen from the data in Table 1 that the capsule-in-capsule gel beads with solidified inner water phase provided by the present invention can effectively improve the stability of water-soluble active substances. Comparing Example 1 with Examples 4-13, it can be seen that when the parameters such as the calcium salt content in the water phase of the Pickering emulsion, the trigger in the oil phase, the oil-water phase volume ratio and the composition of the gel layer change, the stabilizing effect of the water-soluble active substances will be affected; comparing Example 1 with Comparative Examples 1-3, it can be seen that the solidification of the inner water phase of the Pickering emulsion, the combined protection of the particle interface film and the calcium alginate double wall layer can significantly improve the stability of water-soluble active substances.

[0158] Test Example 4

[0159] Determination of DPPH scavenging ability:

[0160] The products prepared in Examples 1-13 and Comparative Examples 1-3 were stored statically at 25°C under 365nm ultraviolet light for 21 days, and the DPPH scavenging ability was tested on days 0, 6, 12 and 21, respectively. A 0.05wt% vitamin C aqueous solution was set as a control group. The test results are shown in Table 2.

[0161] Test method: Take 1g of sample, add 2mL of anhydrous ethanol, mix well, add 2mL of 200μmol / L DPPH solution, mix well, let stand for 30min, filter to get the supernatant, adjust to zero with anhydrous ethanol, and measure the absorbance of the supernatant at 517nm as A i ; In the same way, take 2mL of anhydrous ethanol solvent and 2mL of DPPH solution and mix them to determine the absorbance as A0; then take 1g of the product and add 2mL of anhydrous ethanol, then add 2mL of anhydrous ethanol solvent and mix them, filter and measure the absorbance of the supernatant as A j The free radical scavenging rate is calculated according to the following formula. The greater the DPPH scavenging rate, the stronger the free radical scavenging antioxidant ability of the composition.

[0162] Clearance rate (%) = [1-(A i -A j ) / A0]×100%

[0163] Among them, A j The contribution of the reaction sample itself to the absorbance; A i It is the absorbance value of the sample after the action of DPPH; A0 is the absorption of DPPH itself at the measurement wavelength.

[0164] Table 2

[0165]

[0166] It can be seen from the data in Table 2 that after ultraviolet light treatment, the vitamin C in the capsule-in-capsule beads with solidified inner water phase still has a good DPPH scavenging rate, which proves that the combined protection of the inner water phase solidification, particle interface film and calcium alginate double wall layer of the Pickering emulsion can provide good light protection for water-soluble active substances. When the parameters such as the calcium salt content in the water phase of the Pickering emulsion, the trigger in the oil phase, the oil-water phase volume ratio, and the composition of the gel layer change, they will affect the stabilization effect of the water-soluble active substances, thereby affecting the efficacy of the water-soluble active substances.

[0167] The applicant declares that the present invention illustrates the technical solution of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0168] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0169] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A capsule-in-capsule type gel bead, characterized in that: The capsule-in-capsule gel beads include a water-in-oil type Pickering emulsion loaded with a water-soluble active substance and a calcium alginate gel layer wrapped outside the Pickering emulsion; The water-in-oil type Pickering emulsion comprises a solidified internal water phase, an oil phase and a solid particle emulsifier; The raw materials for preparing the solidified internal water phase include water-soluble active substances, alginate, low dissociation degree calcium salt and water.

2. The capsule-in-capsule type gel beads according to claim 1, characterized in that: The alginate includes sodium alginate and / or potassium alginate; Preferably, the low dissociation calcium salt includes any one or a combination of at least two of calcium disodium edetate, calcium carbonate, calcium sulfate or calcium phosphate; Preferably, the mass ratio of the alginate, the low dissociation degree calcium salt and water is (0.1-1.5):(0.05-2.5):

100.

3. The capsule-in-capsule type gel beads according to claim 1 or 2, characterized in that: The raw materials for preparing the oil phase include an oil solution and a trigger; Preferably, the addition ratio of the triggering agent and the oil solution is (0.5-5) g:100 mL; Preferably, the oil solution comprises any one or a combination of at least two of caprylic / capric triglycerides, white oil or medium-chain fatty acid triglycerides; Preferably, the trigger comprises a weak acid or a lactone; Preferably, the weak acid comprises any one of glacial acetic acid, carbonic acid, citric acid or lactic acid, or a combination of at least two thereof; Preferably, the lactone includes any one of D-glucono-δ-lactone, γ-butyrolactone, ε-caprolactone or δ-valerolactone, or a combination of at least two thereof.

4. The capsule-in-capsule type gel beads according to any one of claims 1 to 3, characterized in that: The solid particle emulsifier is a hydrophobic solid particle emulsifier; Preferably, the hydrophobic solid particle emulsifier comprises hydrophobic silicon dioxide; Preferably, the addition ratio of the solid particle emulsifier to the oil phase is (0.1-1) g:10 mL.

5. The capsule-in-capsule type gel beads according to any one of claims 1 to 4, characterized in that: The volume ratio of the oil phase to the solidified internal water phase in the water-in-oil type Pickering emulsion is 10:(1-16).

6. The capsule-in-capsule type gel beads according to any one of claims 1 to 5, characterized in that: The raw materials for preparing the calcium alginate gel layer include high dissociation degree calcium salt and alginate; Preferably, the high dissociation degree calcium salt includes any one of calcium chloride, calcium bromide, calcium dihydrogen phosphate, calcium lactate or calcium gluconate, or a combination of at least two thereof; Preferably, the alginate comprises sodium alginate and / or potassium alginate.

7. The capsule-in-capsule type gel beads according to any one of claims 1 to 6, characterized in that: The water-in-oil Pickering emulsion is prepared by the following method, which comprises: (1) mixing alginate with water, dissolving it, adding a water-soluble active ingredient, dissolving it, adding a low dissociation degree calcium salt, and obtaining an inner water phase; (2) dissolving a solid particle emulsifier in an oil solution, dispersing the solid particle emulsifier, and adding a triggering agent to obtain an oil phase; (3) The oil phase and the inner water phase are mixed, emulsified, and allowed to stand until the emulsion layer is stable to obtain the water-in-oil type Pickering emulsion.

8. The method for preparing capsule-in-capsule type condensed beads according to any one of claims 1 to 7, characterized in that: The preparation method comprises the following steps: (1) using a water-in-oil type Pickering emulsion as the inner phase liquid; mixing alginate with water and dissolving them to obtain an alginate solution as the outer phase liquid; mixing a high dissociation degree calcium salt with water and dissolving them to obtain a high dissociation degree calcium salt solution as the receiving liquid; (2) The external phase liquid shears the internal phase liquid to form droplets, which are then dropped into the receiving liquid and cross-linked to form calcium alginate beads; (3) The calcium alginate beads are allowed to stand and solidify to obtain the capsule-in-capsule type beads.

9. The method for preparing capsule-in-capsule type condensed beads according to claim 8, characterized in that: The mass fraction of alginate in the alginate solution of step (1) is 1.5-2.5%; Preferably, the mass fraction of the high dissociation degree calcium salt in the high dissociation degree calcium salt solution is 0.5-10%.

10. Use of the capsule-in-capsule type gel beads according to any one of claims 1 to 7 in the preparation of cosmetics.

Images