Astaxanthin microcapsule and method for preparing the same

Abstract

This invention discloses an astaxanthin microcapsule and its preparation method. The method involves extruding astaxanthin raw material with copovidone VA64, glucose, and other excipients in a specific ratio using a twin-screw hot-melt extruder to obtain astaxanthin nano-dispersions, thereby enhancing their water dispersibility and solubility. The astaxanthin nano-dispersions are then suspended in a gelatin solution and subsequently subjected to high-speed homogenization and spray drying to obtain astaxanthin microcapsules. This invention, through the combined use of hot-melt extrusion and spray drying, achieves direct encapsulation of solid astaxanthin, significantly increasing the drug loading capacity of the microcapsules and enhancing the solubility and stability of astaxanthin.

Description

Technical Field

[0001] This invention relates to an astaxanthin microcapsule and its preparation method. Background Technology

[0002] Astaxanthin is a β-carotene mainly found in shrimp, crab, and algae. It is a powerful antioxidant and a safe food additive, used as a natural colorant in food and flavorings. However, due to its structure containing a long conjugated double bond and unsaturated ketone and hydroxyl groups at the ends of the double bond, it is easily inactivated by light, heat, and oxygen. Furthermore, astaxanthin is a nonpolar substance, insoluble in water and only slightly soluble in oils, making its formulation development challenging and significantly limiting its applications.

[0003] Microencapsulation technology is a technique that encapsulates solid, liquid, or gaseous substances within a microscopic, closed system. This method not only isolates and protects the encapsulated substance from light and oxygen, slowing down oxidation and thus improving its stability, but also effectively masks the distinctive odor of the core material and controls the drug release rate. Therefore, astaxanthin can be encapsulated using microencapsulation technology to improve its storage stability.

[0004] Microcapsule preparation methods can be categorized into physical, chemical, and physicochemical methods, with common methods including single-condensation, complex-condensation, spray drying, spray condensation, and suspension coating. Spray drying is a widely used microcapsule preparation technique. This method disperses liquid materials into extremely fine mist-like particles through mechanical action, then dries them with heated gas to obtain the final dried microparticle product. The characteristics of spray drying technology are: it directly converts liquid materials into powdered products, enabling continuous batch production, and obtaining products with uniform particle size and good dispersibility without a crushing process.

[0005] Because astaxanthin is relatively stable in oil solutions, current methods for preparing astaxanthin microcapsules generally involve dissolving astaxanthin in an oil phase, emulsifying the astaxanthin oil with an aqueous phase, and then spray-drying. For example, patent document CN111358762A uses astaxanthin oil as the core material and modified starch and β-cyclodextrin as the encapsulation material for spray drying; CN101292965B dissolves astaxanthin in fatty acid glycerides and embeds it in gelatin for spray drying; CN1048056051 uses sodium methylcellulose and modified starch to embed astaxanthin oil for spray drying, etc. However, this method results in low drug loading and a small content of the active ingredient, leading to large dosages in the finished product. Directly encapsulating solid astaxanthin into microcapsules is a method to increase the drug loading of the microcapsules and reduce the dosage of the product. However, this method has limitations: astaxanthin solids have poor stability and require high encapsulation efficiency; the excessive hydrophobicity of astaxanthin solids makes it difficult to achieve uniform suspension, resulting in significant encapsulation challenges and low encapsulation efficiency; furthermore, the large particle size of astaxanthin dispersed in the microcapsules leads to slow dissolution and affects its bioavailability. Therefore, new technologies are needed to enhance the water dispersibility of astaxanthin solids and reduce their particle size to simplify encapsulation.

[0006] Hot melt extrusion technology can nanoscale drugs through the action of shear force and heat, thereby improving the water dispersibility and solubility of the drugs. This invention utilizes a preferred hot melt extrusion process to transform astaxanthin solids into nano-sized particles dispersed in a carrier, reducing particle size, improving sphericity, and enhancing water dispersibility. This also reduces the difficulty of encapsulation. After being fully dispersed in water, the astaxanthin is then encapsulated using gelatin, resulting in astaxanthin microcapsules with excellent solubility.

[0007] This technology solves the problem of the difficulty in directly encapsulating astaxanthin solids. Astaxanthin microcapsules with high drug loading capacity prepared by nano-processing of astaxanthin solids have good stability and good water dispersibility and solubility. Summary of the Invention

[0008] The purpose of this invention is to provide astaxanthin microcapsules and a method for their preparation. This invention utilizes a combination of hot-melt extrusion and spray drying techniques to obtain astaxanthin microcapsules with good stability and water dispersibility.

[0009] The technical solution of the present invention is as follows:

[0010] An astaxanthin microcapsule is made from the following raw materials in the indicated weight percentages: astaxanthin 5-25%, PVP VA64 1.67-8.33%, glucose 3.33-16.67%, and gelatin 50-90%; the total of all raw materials is 100%.

[0011] Furthermore, the preferred mass ratio of astaxanthin, PVP VA64, and glucose is 3:1:2.

[0012] The preparation method of the astaxanthin microcapsules of the present invention is as follows:

[0013] (1) Mix astaxanthin, PVP VA64 and glucose evenly, extrude the mixture in a twin-screw hot melt extruder, cool the extrudate to room temperature and disperse it in water to obtain an extrudate suspension;

[0014] The process conditions for hot melt extrusion are: extrusion temperature 100℃, screw speed 30rpm;

[0015] The preferred mass ratio of extrudate to water is 1:20;

[0016] (2) Add gelatin to water to swell and dissolve, and obtain a gelatin solution;

[0017] The preferred mass ratio of gelatin to water is 1 to 5:20;

[0018] (3) The gelatin solution obtained in step (2) and the extrudate suspension obtained in step (1) are added to a mortar and mixed and ground. Then, high-speed homogenization is performed, and finally spray drying is performed to obtain astaxanthin microcapsules.

[0019] The preferred mixing and grinding time is 5 minutes;

[0020] The optimal parameters for high-speed homogenization are: 10000 rpm, 3–15 min;

[0021] The preferred parameters for spray drying are: drying temperature 130–190℃, feed rate 1.6–6.4 mL / min, and atomizing gas flow rate 439 L / h.

[0022] The key technical points of this invention are:

[0023] 1. In the raw material formulation, the ratio of astaxanthin, PVP VA64, and glucose must be 3:1:2; otherwise, nanoscale dispersion cannot be formed, thus failing to effectively improve dispersibility and solubility. This is because PVP VA64 plays a role in separating and isolating the drug (astaxanthin) during hot melt extrusion; glucose acts as a filler and increases the extruder torque. During extrusion, the drug is sheared and broken into nanoscale particles. An appropriate proportion of glucose can increase the extruder torque and shear force, while PVP VA64 effectively isolates the broken drug particles, maintaining the drug particle size at the nanoscale.

[0024] 2. The extrusion temperature should be 100℃. Too low a temperature will result in excessive torque, causing the extruder to stop, while too high a temperature will result in insufficient torque and insufficient shear force, thus failing to achieve nanoscale dispersion.

[0025] The beneficial effects of this invention are as follows:

[0026] This invention achieves direct encapsulation of solid astaxanthin by combining hot melt extrusion and spray drying, which greatly increases the drug loading capacity of microcapsules and enhances the solubility and stability of astaxanthin. Attached Figure Description

[0027] Figure 1 Water dispersion of the active pharmaceutical ingredient (a) and microcapsules (b).

[0028] Figure 2 : Microcapsule water dispersion particle size data; (a) - strong mean data, (b) - number mean data, (c) - volume mean data.

[0029] Figure 3 Results of UV stability testing of the active pharmaceutical ingredient and microcapsules. Detailed Implementation

[0030] The present invention is further described below through specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0031] In the following embodiments,

[0032] Astaxanthin raw material is from Zhejiang Medicine, and PVP VA64 is from BASF. VA64.

[0033] Example 1:

[0034] Astaxanthin raw material was mixed with PVP VA64 and glucose in a ratio of 3:1:2 (by mass). The mixture was then extruded in a twin-screw hot melt extruder at a screw speed of 30 rpm and an extrusion temperature of 100°C.

[0035] Add 3g of gelatin to 20ml of water and swell and dissolve it in a 37℃ water bath. Add 1.04g of extrudate to 20ml of water and disperse it in a 37℃ water bath.

[0036] Add the gelatin solution and the extrudate suspension to a mortar and grind for 5 minutes. Then, homogenize the ground suspension at 10,000 rpm for 10 minutes.

[0037] The homogenized suspension was spray-dried at an inlet air temperature of 150℃, a feed rate of 3.2 ml / min, and an atomizing gas flow rate of 439 L / h, and the finished product was collected.

[0038] Example 2:

[0039] Astaxanthin raw material was mixed with PVP VA64 and glucose in a ratio of 3:1:2. The mixture was then extruded in a twin-screw hot melt extruder at a screw speed of 30 rpm and an extrusion temperature of 100°C.

[0040] Add 4g of gelatin to 20ml of water to swell and dissolve, and add 1.04g of extrudate to 20ml of water to disperse.

[0041] Add the gelatin solution and the extrudate suspension to a mortar and grind for 5 minutes. Then, homogenize the ground suspension at 10,000 rpm for 5 minutes.

[0042] The homogenized suspension was spray-dried at an inlet air temperature of 130℃, a feed rate of 1.6 ml / min, and an atomizing gas flow rate of 439 L / h, and the finished product was collected.

[0043] Example 3:

[0044] Astaxanthin raw material was mixed with PVP VA64 and glucose in a ratio of 3:1:2. The mixture was then extruded in a twin-screw hot melt extruder at a screw speed of 30 rpm and an extrusion temperature of 100°C.

[0045] Add 4g of gelatin to 20ml of water to swell and dissolve, and add 1.04g of extrudate to 20ml of water to disperse.

[0046] Add the gelatin solution and the extrudate suspension to a mortar and grind for 5 minutes. Then, homogenize the ground suspension at 10,000 rpm for 5 minutes.

[0047] The homogenized suspension was spray-dried at an inlet air temperature of 130℃, a feed rate of 3.2 ml / min, and an atomizing gas flow rate of 439 L / h, and the finished product was collected.

[0048] Example 4:

[0049] Astaxanthin raw material was mixed with PVP VA64 and glucose in a ratio of 3:1:2. The mixture was then extruded in a twin-screw hot melt extruder at a screw speed of 30 rpm and an extrusion temperature of 100°C.

[0050] Add 4g of gelatin to 20ml of water and swell and dissolve it in a 37℃ water bath. Add 1.04g of extrudate to 20ml of water and disperse it in a 37℃ water bath.

[0051] Add the gelatin solution and the extrudate suspension to a mortar and grind for 5 minutes. Then, homogenize the ground suspension at 10,000 rpm for 3 minutes.

[0052] The homogenized suspension was spray-dried at an inlet air temperature of 150℃, a feed rate of 3.2 ml / min, and an atomizing gas flow rate of 439 L / h, and the finished product was collected.

[0053] Example 5:

[0054] Astaxanthin raw material was mixed with PVP VA64 and glucose in a ratio of 3:1:2. The mixture was then extruded in a twin-screw hot melt extruder at a screw speed of 30 rpm and an extrusion temperature of 100°C.

[0055] Add 4g of gelatin to 20ml of water to swell and dissolve, and add 1.04g of extrudate to 20ml of water to disperse.

[0056] Add the gelatin solution and the extrudate suspension to a mortar and grind for 5 minutes. Then, homogenize the ground suspension at 10,000 rpm for 5 minutes.

[0057] The homogenized suspension was spray-dried at an inlet air temperature of 150℃, a feed rate of 3.2 ml / min, and an atomizing gas flow rate of 439 L / h, and the finished product was collected.

[0058] Example 6:

[0059] Astaxanthin raw material was mixed with PVP VA64 and glucose in a ratio of 3:1:2. The mixture was then extruded in a twin-screw hot melt extruder at a screw speed of 30 rpm and an extrusion temperature of 100°C.

[0060] Add 4g of gelatin to 20ml of water to swell and dissolve, and add 1.04g of extrudate to 20ml of water to disperse.

[0061] Add the gelatin solution and the extrudate suspension to a mortar and grind for 5 minutes. Then, homogenize the ground suspension at 10,000 rpm for 15 minutes.

[0062] The homogenized suspension was spray-dried at an inlet air temperature of 150℃, a feed rate of 3.2 ml / min, and an atomizing gas flow rate of 439 L / h, and the finished product was collected.

[0063] Example 7:

[0064] Astaxanthin raw material was mixed with PVP VA64 and glucose in a ratio of 3:1:2. The mixture was then extruded in a twin-screw hot melt extruder at a screw speed of 30 rpm and an extrusion temperature of 100°C.

[0065] Add 5g of gelatin to 20ml of water and swell and dissolve it in a 37℃ water bath. Add 1.04g of extrudate to 20ml of water and disperse it in a 37℃ water bath.

[0066] Add the gelatin solution and the extrudate suspension to a mortar and grind for 5 minutes. Then, homogenize the ground suspension at 10,000 rpm for 10 minutes.

[0067] The homogenized suspension was spray-dried at an inlet air temperature of 150℃, a feed rate of 3.2 ml / min, and an atomizing gas flow rate of 439 L / h, and the finished product was collected.

[0068] Example 8:

[0069] Astaxanthin raw material was mixed with PVP VA64 and glucose in a ratio of 3:1:2. The mixture was then extruded in a twin-screw hot melt extruder at a screw speed of 30 rpm and an extrusion temperature of 100°C.

[0070] Add 4g of gelatin to 20ml of water to swell and dissolve, and add 1.04g of extrudate to 20ml of water to disperse.

[0071] Add the gelatin solution and the extrudate suspension to a mortar and grind for 5 minutes. Then, homogenize the ground suspension at 10,000 rpm for 5 minutes.

[0072] The homogenized suspension was spray-dried at an inlet air temperature of 170℃, a feed rate of 3.2 ml / min, and an atomizing gas flow rate of 439 L / h, and the finished product was collected.

[0073] Example 9:

[0074] Astaxanthin raw material was mixed with PVP VA64 and glucose in a ratio of 3:1:2. The mixture was then extruded in a twin-screw hot melt extruder at a screw speed of 30 rpm and an extrusion temperature of 100°C.

[0075] Add 4g of gelatin to 20ml of water to swell and dissolve, and add 1.04g of extrudate to 20ml of water to disperse.

[0076] Add the gelatin solution and the extrudate suspension to a mortar and grind for 5 minutes. Then, homogenize the ground suspension at 10,000 rpm for 5 minutes.

[0077] The homogenized suspension was spray-dried at an inlet air temperature of 190℃, a feed rate of 3.2 ml / min, and an atomizing gas flow rate of 439 L / h, and the finished product was collected.

[0078] Example 10:

[0079] Astaxanthin raw material was mixed with PVP VA64 and glucose in a ratio of 3:1:2. The mixture was then extruded in a twin-screw hot melt extruder at a screw speed of 30 rpm and an extrusion temperature of 100°C.

[0080] Add 4g of gelatin to 20ml of water and swell and dissolve it in a 37℃ water bath. Add 1.04g of extrudate to 20ml of water and disperse it in a 37℃ water bath.

[0081] Add the gelatin solution and the extrudate suspension to a mortar and grind for 5 minutes. Then, homogenize the ground suspension at 10,000 rpm for 10 minutes.

[0082] The homogenized suspension was spray-dried at an inlet air temperature of 150℃, a feed rate of 3.2 ml / min, and an atomizing gas flow rate of 439 L / h, and the finished product was collected.

[0083] Example 11:

[0084] Astaxanthin raw material was mixed with PVP VA64 and glucose in a ratio of 3:1:2. The mixture was then extruded in a twin-screw hot melt extruder at a screw speed of 30 rpm and an extrusion temperature of 100°C.

[0085] Add 4g of gelatin to 20ml of water to swell and dissolve, and add 1.04g of extrudate to 20ml of water to disperse.

[0086] Add the gelatin solution and the extrudate suspension to a mortar and grind for 5 minutes. Then, homogenize the ground suspension at 10,000 rpm for 5 minutes.

[0087] The homogenized suspension was spray-dried at an inlet air temperature of 130℃, a feed rate of 4.8L / min, and an atomizing gas flow rate of 439L / h, and the finished product was collected.

[0088] Example 12:

[0089] Astaxanthin raw material was mixed with PVP VA64 and glucose in a ratio of 3:1:2. The mixture was then extruded in a twin-screw hot melt extruder at a screw speed of 30 rpm and an extrusion temperature of 100°C.

[0090] Add 4g of gelatin to 20ml of water to swell and dissolve, and add 1.04g of extrudate to 20ml of water to disperse.

[0091] Add the gelatin solution and the extrudate suspension to a mortar and grind for 5 minutes. Then, homogenize the ground suspension at 10,000 rpm for 5 minutes.

[0092] The homogenized suspension was spray-dried at an inlet air temperature of 130℃, a feed rate of 6.4 ml / min, and an atomizing gas flow rate of 439 L / h, and the finished product was collected.

[0093] Example 13:

[0094] Drug loading and encapsulation efficiency were investigated: The microcapsules prepared in Examples 1-12 were dissolved in dimethyl sulfoxide and their absorbance was measured at a wavelength of 481 nm to calculate their content; the microcapsules were washed with dichloromethane and the amount of astaxanthin in the washing solution was measured as unencapsulated astaxanthin. The results of drug loading and encapsulation efficiency are shown in Table 1.

[0095] Table 1: Drug loading and encapsulation efficiency of microcapsules in Examples 1-12

[0096] Example Drug loading Encapsulation rate Example 1 13.10％ 48.46％ Example 2 11.04％ 61.80％ Example 3 10.27％ 53.20％ Example 4 11.77％ 59.43％ Example 5 11.26％ 68.58％ Example 6 10.99％ 68.91％ Example 7 9.40％ 51.17％ Example 8 10.54％ 57.30％ Example 9 10.64％ 57.80％ Example 10 10.98％ 69.04％ Example 11 10.85％ 68.89％ Example 12 11.68％ 70.03％

[0097] Water dispersibility and solubility assessment: Astaxanthin raw material and the microcapsules of Example 12 were dispersed in water, and their dispersion state was observed by photographing. The mixture was then filtered through a 0.22 μm filter membrane, and its absorbance was measured at a wavelength of 481 nm. The solubility was calculated, and the results are shown below. Figure 1 As shown in Table 2, astaxanthin raw material has strong hydrophobicity. When added to water, it floats on the surface and cannot enter the water. Its solubility in water is only 0.006 μg / mL. However, astaxanthin microcapsules can be quickly dispersed in water after being added, and the entire water body turns red. Its solubility is 28 μg / mL.

[0098] Table 2: Solubility of Active Pharmaceutical Ingredient and Microcapsules

[0099] microcapsules Solubility: 28ug / ml raw materials Solubility: 0.006 ug / ml

[0100] Astaxanthin particle size distribution determination: Astaxanthin microcapsules were dispersed in water, and their particle size was measured using a Malvern particle size analyzer. The results are shown below. Figure 2 This shows that the strength, volume, and number of particles are all at the nanoscale, further proving that the water dispersibility has been enhanced through extrusion technology.

[0101] Table 3: Dispersible particle size of microcapsules in water

[0102] Qiang Jun Mean Body average Particle size 449.6nm 286.5nm 798.4nm

[0103] Stability test: The active pharmaceutical ingredient and the microcapsules of Example 12 were placed under direct ultraviolet light for 5 days, and their retention rate was measured daily. The results are shown in the figure. Figure 3 .

[0104] Comparative Example 1:

[0105] Add 3g of gelatin and 1g of glucose to 20ml of water to swell and dissolve; add 0.5g of astaxanthin solid to 20ml of water to disperse.

[0106] The astaxanthin dispersion was added to the gelatin glucose solution and mixed evenly. The suspension was then homogenized at 10,000 rpm for 5 minutes.

[0107] The homogenized suspension was spray-dried at an inlet air temperature of 130℃, a feed rate of 3.2 ml / min, and an atomizer flow rate of 439 L / h, and the finished product was collected.

[0108] Comparative Example 2:

[0109] Add 3g of gelatin and 1g of glucose to 20ml of water to swell and dissolve; add 0.5g of astaxanthin solid and 0.02g of Tween 20 to 20ml of water to disperse.

[0110] Add the dispersion of astaxanthin and Tween 20 to the gelatin glucose solution and mix well. Then homogenize the suspension at 10,000 rpm for 5 minutes.

[0111] The homogenized suspension was spray-dried at an inlet air temperature of 130℃, a feed rate of 3.2 ml / min, and an atomizer flow rate of 439 L / h, and the finished product was collected.

[0112] Comparative Example 3:

[0113] Add 3g of gelatin and 1g of glucose to 20ml of water and let them swell and dissolve.

[0114] Astaxanthin solid was directly added to gelatin glucose solution and ground for 5 minutes. The suspension was then homogenized at 10,000 rpm for 5 minutes.

[0115] The homogenized suspension was spray-dried at an inlet air temperature of 130℃, a feed rate of 3.2 ml / min, and an atomizer flow rate of 439 L / h, and the finished product was collected.

[0116] Comparative Example 4:

[0117] Add 3g of gelatin and 1g of glucose to 20ml of water to swell and dissolve; pre-grind the astaxanthin for 5 minutes.

[0118] Add the gelatin glucose solution to the ground astaxanthin and mix and grind for 5 minutes. Then homogenize the suspension at 10,000 rpm for 5 minutes.

[0119] The homogenized suspension was spray-dried at an inlet air temperature of 130℃, a feed rate of 3.2 ml / min, and an atomizer flow rate of 439 L / h, and the finished product was collected.

[0120] The microcapsules in Comparative Examples 1-4 were dissolved in dimethyl sulfoxide, and their absorbance was measured at a wavelength of 481 nm to calculate their content. The microcapsules were washed with dichloromethane, and the amount of astaxanthin in the washing solution was measured as unencapsulated astaxanthin. The drug loading and encapsulation efficiency were calculated and the results are shown in Table 4.

[0121] Table 4: Drug loading and encapsulation efficiency of microcapsules in Comparative Examples 1-4

[0122] Comparative Example Drug loading Encapsulation rate Comparative Example 1 10.72％ 23.98％ Comparative Example 2 10.25％ 30.60％ Comparative Example 3 8.50％ 30.74％ Comparative Example 4 10.54％ 51.85％

[0123] Compared with the examples, the encapsulation rate was significantly lower, indicating that the hot melt extrusion technology effectively reduced the encapsulation difficulty of astaxanthin solids and improved the encapsulation rate of microcapsules.

Claims

1. An astaxanthin microcapsule, characterized in that, It is made from the following raw materials in the indicated weight percentages: astaxanthin 5-25%, PPVVA64 1.67-8.33%, glucose 3.33-16.67%, gelatin 50-90%; the total weight of all raw materials is 100%. The mass ratio of astaxanthin, PVP, VA64, and glucose is 3:1:2; The astaxanthin microcapsules are prepared as follows: (1) Mix astaxanthin, PVP VA64 and glucose evenly, and extrude the mixture in a twin-screw hot melt extruder at an extrusion temperature of 100°C and a screw speed of 30 rpm. After the extrudate is cooled to room temperature, it is dispersed in water to obtain an extrudate suspension. (2) Add gelatin to water to swell and dissolve, and obtain a gelatin solution; (3) The gelatin solution obtained in step (2) and the extrudate suspension obtained in step (1) are added to a mortar and mixed and ground. Then, high-speed homogenization is performed, and finally spray drying is performed to obtain astaxanthin microcapsules.

2. The astaxanthin microcapsules as described in claim 1, characterized in that, In step (1) of the preparation method, the mass ratio of extrudate to water is 1:

20.

3. The astaxanthin microcapsules as described in claim 1, characterized in that, In step (2) of the preparation method, the mass ratio of gelatin to water is 1~5:

20.

4. The astaxanthin microcapsules as described in claim 1, characterized in that, In step (3) of the preparation method, the mixing and grinding time is 5 min.

5. The astaxanthin microcapsules as described in claim 1, characterized in that, In step (3) of the preparation method, the parameters for high-speed homogenization are set as follows: 10000 rpm, 3~15 min.

6. The astaxanthin microcapsules as described in claim 1, characterized in that, In step (3) of the preparation method, the parameters for spray drying are set as follows: drying temperature 130~190℃, feed rate 1.6~6.4mL / min, and atomizing gas flow rate 439L / h.

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