Zinc lutein gluconate vitamin A soft capsule and its production process

Abstract

This invention relates to the field of health food processing technology, specifically to a lutein-zinc gluconate-vitamin A soft capsule and its production process. This invention uses marigold processing byproduct pollen as raw material, employing aqueous flotation for efficient impurity removal, combined with airflow flash drying technology. High-temperature, short-time treatment minimizes the thermal degradation loss of lutein, while simultaneously obtaining uniformly sized pollen, providing a good mass transfer basis for subsequent supercritical extraction, achieving resource utilization of waste, and significantly reducing raw material costs. This invention uses a composite carrier oil composed of safflower seed oil, soybean lecithin, and natural vitamin E to construct a self-emulsifying dispersion system, significantly improving the bioavailability of lutein; simultaneously, it provides synergistic antioxidant effects, and with demetallization treatment, forms multiple stabilizing barriers, extending the product's shelf life. The formula combines zinc gluconate and vitamin A acetate, which work synergistically to protect the eyes from multiple dimensions, including macular protection, photosensitizer synthesis, and retinal metabolism, significantly enhancing the product's functional value.

Description

Technical Field

[0001] This invention relates to the field of health food processing technology, specifically to a lutein-zinc gluconate vitamin A soft capsule and its production process. Background Technology

[0002] Lutein is a natural, fat-soluble carotenoid and a core pigment component of the macula in the human retina. It can filter blue light and antagonize photo-oxidative damage, playing a clear physiological role in relieving eye fatigue, delaying macular degeneration, and improving visual function. Vitamin A is a key component of photosensitive substances in visual cells; deficiency can lead to decreased dark adaptation and dry eye. Zinc gluconate contains zinc, which participates in retinal metabolism and retinol transport, playing an important synergistic role in maintaining normal visual function. The combination of these three ingredients can synergistically protect the eyes from multiple dimensions, including macular protection, photosensitive substance synthesis, and metabolic support, making it an optimal formula for functional eye-protecting foods.

[0003] Marigolds are a primary raw material for the industrial extraction of lutein. Marigold flowers are the main byproduct of lutein extraction and processing, still containing 15%-25% lutein, as well as active ingredients such as flavonoids, phytosterols, and unsaturated fatty acids. Currently, most marigold flowers are directly discarded or treated as low-value animal feed, resulting in a waste of biological resources and environmental pressure from solid waste disposal. Extracting and purifying lutein from marigold flowers is an important way to achieve high-value utilization of processing byproducts, offering both economic and environmental benefits.

[0004] Existing lutein extraction technologies mainly include organic solvent extraction, enzymatic-assisted extraction, and supercritical CO2 extraction. Organic solvent extraction suffers from drawbacks such as solvent residue, poor safety, and low product purity; enzymatic extraction has a long processing cycle, high cost, and is prone to introducing contaminating microorganisms, making it difficult to scale up production; supercritical CO2 extraction leaves no solvent residue and operates under mild conditions, making it the mainstream technology for lutein extraction. However, traditional single-stage supercritical extraction is difficult to effectively separate light impurities such as waxes and free fatty acids, and marigolds naturally contain Fe... 3+ Cu 2+ Transition metal ions can enter the oleoresin during extraction, acting as an oxidation catalyst to accelerate the breakage of the conjugated double bonds of lutein, resulting in poor product storage stability. After being sealed and stored at room temperature for 3 months, the lutein retention rate is usually less than 55%, which seriously restricts the product's shelf life.

[0005] To address the oxidative degradation caused by residual metal ions, existing technologies primarily employ methods such as activated carbon adsorption, conventional ion exchange resins, and EDTA complexation. However, activated carbon adsorption suffers from poor selectivity, leading to the simultaneous adsorption of lutein and significant loss of active ingredients. Conventional ion exchange resins exhibit low mass transfer efficiency in oil-phase systems, resulting in limited metal removal. Furthermore, conventional complexing agents like EDTA pose a risk of oil-phase residue and lack sufficient chelation selectivity, failing to meet the safety and stability requirements of high-end health foods. In addition, existing lutein soft capsules often use common plant oils as the sole carrier oil, resulting in poor lutein dispersibility, low bioavailability, and a lack of a multi-dimensional antioxidant protection system, thus failing to fundamentally address the industry's pain point of oxidative deterioration during storage.

[0006] Therefore, developing a lutein complex soft capsule preparation process that can efficiently and specifically remove transition metal ions, simultaneously improve the purity and storage stability of lutein, and realize the high-value utilization of marigold resources has important industrial application value. Summary of the Invention

[0007] To address the problems existing in the prior art, the purpose of this invention is to provide a lutein-zinc gluconate vitamin A soft capsule and its manufacturing process.

[0008] The objective of this invention is achieved through the following technical solution: In a first aspect, the present invention provides a manufacturing process for lutein zinc gluconate vitamin A soft capsules, comprising the following steps: Step 1, Flower residue separation and pretreatment: Marigold flowers are placed in water for flotation to remove heavy impurities such as flower stems and mud, and the floating petal components are collected. The petal components are dehydrated to control the moisture content to 68%-75%. The dehydrated petals are then flash-dried using airflow at 130-170℃. After drying, they are pulverized to obtain marigold flower powder. Preferably, the dehydration process can be performed by using a vibrating screen for draining or by low-pressure pressing with a press; the final marigold pollen has a moisture content of 4%-12% and a particle size that meets the requirement that more than 50% of the particles pass through a 60-mesh standard sieve, ensuring the mass transfer efficiency of subsequent extraction.

[0009] Step 2, supercritical carbon dioxide extraction: Marigold pollen was fed into an extraction vessel, and food-grade carbon dioxide was introduced. The first stage of extraction was carried out under near-critical conditions of 30-32℃ and 7.0-7.3MPa for 0.5-1h, selectively dissolving and removing light impurities such as waxes and free fatty acids. The extract from this stage was then separated and discarded. Subsequently, the temperature and pressure of the extraction vessel were increased to 42-52℃ and 28-38MPa for the second stage of extraction for 1.5-3.5h, after which crude lutein oleoresin was obtained.

[0010] Step 3, chelation complexation and demetallization: Crude lutein oleoresin was diluted with food-grade n-hexane at a mass ratio of 1:7-11 and stirred to dissolve, yielding a crude resin solution. 0.6%-2.2% of a glucosamine carboxyphosphonic acid complexing agent was weighed and dissolved in deionized water to prepare a 6%-12% aqueous complexing agent solution. The aqueous complexing agent solution was added to the crude resin solution, and the mixture was stirred vigorously at 32-38℃ for 25-55 minutes. The mixture was then allowed to stand and separated. The organic phase was washed 2-3 times with an equal volume of deionized water, and the organic phase was separated. Anhydrous sodium sulfate was added for drying, and the mixture was filtered. The filtrate was subjected to reduced pressure rotary evaporation at 36-42℃ and a vacuum of 0.07-0.09 MPa to recover n-hexane, yielding the demetallized crude lutein oleoresin.

[0011] Preferably, the glucosamine carboxyphosphonic acid complexing agent has a positive effect on Fe. 3+ Cu 2+ Transition metal ions have a specific chelating effect and do not cause adsorption loss of fat-soluble active ingredients such as lutein, β-carotene, and vitamin A.

[0012] Preferably, the Fe in the oleoresin after step 3 treatment is... 3+ Removal rate ≥96%, Cu 2+ Removal rate ≥93%.

[0013] Step 4, gradient distillation purification: The crude demetallized lutein oleoresin was fed into a vacuum distillation vessel protected by nitrogen. High-purity nitrogen was purged throughout the process to maintain a slight positive pressure inside the vessel. Distillation was carried out for 3-4 hours under vacuum conditions of 0.08-0.095 MPa and material temperature of 40-50℃ to remove free water and low-boiling-point off-odor components. The dehydrated oleoresin was then fed into a short-path molecular distillation apparatus. The system was purged with nitrogen to replace oxygen throughout the process. The vacuum degree was controlled at 0.5-2 Pa, the evaporation surface temperature at 120-130℃, and the feed rate at 8-12 mL / min to remove light oil components. The heavy phase components were collected to obtain high-purity lutein oleoresin.

[0014] Preferably, the nitrogen gas in the vacuum distillation vessel is maintained at a slightly positive pressure of 0.01 MPa; after vacuum distillation, the water content of the oleoresin is reduced to below 2%; short-path molecular distillation removes about 25%-35% of the light oil components.

[0015] Step 5, Compound formulation of active ingredients and preparation of soft capsules: High-purity lutein oleoresin, zinc gluconate, vitamin A acetate, and composite carrier oil are added to a mixing tank in proportion and mixed for 25-35 minutes under nitrogen protection and low-speed stirring at 35-40℃ to form a homogeneous and stable self-emulsifying oil mixture, which is the soft capsule core. The core and the capsule shell glue liquid are fed into a rotary pelleting machine, pressed into shape, and then shaped, dried in a rotating drum, washed with alcohol, and air-dried to obtain the finished lutein zinc gluconate vitamin A soft capsule.

[0016] Preferably, the composite carrier oil is composed of safflower seed oil, soybean lecithin, and natural vitamin E in a mass ratio of 82-90:6-12:2-6.

[0017] Preferably, the capsule shell solution is prepared by mixing gelatin, glycerin, and purified water in a mass ratio of 1:0.3-0.6:1-2, and potassium sorbate is added at 0.02%-0.2% of the dry weight of the capsule shell as a preservative.

[0018] Preferably, the preparation method of the glucosamine carboxyphosphonic acid complexing agent includes: S1. Dissolve D-glucosamine in deionized water, add phosphorous acid, stir well, and then add concentrated hydrochloric acid. The amount of concentrated hydrochloric acid is 0.6-1.0 times the mass of D-glucosamine. Heat to reflux, and slowly add formaldehyde aqueous solution. After the addition is complete, continue to keep the mixture at reflux for 4-6 hours. After the reaction is completed, concentrate under reduced pressure to remove more than 80% of the water and hydrochloric acid. Dissolve the concentrate in anhydrous methanol, and slowly add acetone while stirring until the mixture becomes turbid and the precipitation is complete. Let it stand, filter, wash the filter cake with a small amount of cold methanol, and dry under vacuum to obtain N-phosphonic acid methylglucosamine solid. Preferably, in S1, the mass ratio of D-glucosamine, phosphorous acid, and formaldehyde is 1:0.50-0.60:0.17-0.20; more preferably, it is 1:0.53:0.18. S2. Dissolve N-phosphonic acid methyl glucosamine solid in anhydrous methanol, add triethylamine as an acid-binding agent, and slowly add a methanol solution of tert-butyl bromoacetate dropwise under ice bath cooling. The addition is completed within 1 hour. The mixture is then heated to room temperature and stirred for 7-13 hours. The triethylamine hydrobromide is removed by filtration, the filtrate is concentrated, and purified by column chromatography to obtain the glucosamine intermediate. Preferably, in S2, the mass ratio of D-glucosamine, triethylamine, and tert-butyl bromoacetate, based on D-glucosamine, is 1:1.2-1.8:2.0-2.8.

[0019] S3. Dissolve the glucosamine intermediate in dichloromethane, add trifluoroacetic acid (5-10 times the mass of the intermediate), stir at room temperature for 4-8 hours, and remove the solvent and excess trifluoroacetic acid by vacuum evaporation. Dissolve the residue in a small amount of water, adjust the pH to 4.5-5.5 with sodium hydroxide solution, add anhydrous ethanol to precipitate the product, let stand, filter, recrystallize twice with an ethanol-water mixed solvent (volume ratio 1:1-2), and dry under vacuum at room temperature to obtain the target product, glucosamine carboxyphosphonic acid complexing agent.

[0020] Secondly, the present invention provides a lutein zinc gluconate vitamin A soft capsule, which is prepared by the above-described preparation method.

[0021] The beneficial effects of this invention are as follows: 1. This invention uses marigold processing by-product pollen residue as raw material, and efficiently removes impurities through aqueous flotation, combined with airflow flash drying technology. High-temperature short-time treatment minimizes the thermal degradation loss of lutein, while obtaining pollen with uniform particle size, providing a good mass transfer basis for subsequent supercritical extraction, realizing the resource utilization of waste and significantly reducing raw material costs.

[0022] 2. This invention employs a two-stage supercritical CO2 extraction process. In the first stage, under near-critical conditions, light impurities such as waxes and free fatty acids are selectively removed to avoid interference with subsequent purification. In the second stage, lutein is extracted under high pressure and high efficiency, with no organic solvent residue throughout the process. The product is highly safe, and the purity and impurity separation effect are significantly better than traditional single-stage extraction.

[0023] 3. The glucosamine-carboxyphosphonic acid complexing agent used in this invention uses natural D-glucosamine as its backbone, while introducing double chelating sites for carboxyl and phosphonic acid groups, supplemented by the coordination effect of hydroxyl groups on the sugar ring. The chelation selectivity and binding force are significantly better than conventional complexing agents such as EDTA and citric acid, and the metal removal rate can reach more than 96%. This complexing agent has strong molecular polarity, extremely low oil phase residue, and no adsorption loss of fat-soluble active ingredients such as lutein and vitamin A, thus eliminating the core inducing factor of metal ion catalytic oxidation from the root.

[0024] 4. This invention employs a gradient purification process combining vacuum distillation and short-path molecular distillation. Nitrogen is used to isolate oxygen throughout the process. First, moisture and odor components are removed at low temperature, and then light oils are removed under high vacuum. The material is heated for a short time and at a low temperature, which effectively avoids thermal degradation and oxidation of lutein. The final product has high purity, bright color, and no unpleasant odor.

[0025] 5. This invention utilizes a composite carrier oil made from safflower seed oil, soybean lecithin, and natural vitamin E to construct a self-emulsifying dispersion system, significantly improving the bioavailability of lutein. Simultaneously, it provides synergistic antioxidant effects, and the metal removal process forms multiple stabilizing barriers, extending the product's shelf life. The formula also incorporates zinc gluconate and vitamin A acetate; these three components work synergistically to protect the eyes from multiple dimensions, including macular protection, photosensitizer synthesis, and retinal metabolism, significantly enhancing the product's functional value.

[0026] 6. The process parameters of each step in this invention are controllable, and the equipment used are all general equipment in the food processing industry. No special customization is required, which can realize continuous and large-scale production, and the batch quality of the products is stable and meets the national food safety production standards. Detailed Implementation

[0027] The technical solution of the present invention is illustrated below through specific examples. It should be understood that the one or more method steps mentioned in the present invention do not preclude the existence of other method steps before or after the combined steps, or the insertion of other method steps between these explicitly mentioned steps; it should also be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the present invention. Furthermore, unless otherwise stated, the numbering of each method step is merely a convenient tool for identifying each method step, and not for limiting the order of the method steps or defining the scope of the present invention. Changes or adjustments to their relative relationships, without substantially altering the technical content, should also be considered within the scope of the present invention.

[0028] To better understand the above technical solutions, exemplary embodiments of the present invention are described in more detail below. While exemplary embodiments of the present invention are shown, it should be understood that the present invention can be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided to enable a more thorough understanding of the present invention and to fully convey the scope of the invention to those skilled in the art.

[0029] The present invention will be further described below with reference to the following embodiments.

[0030] Example 1 A manufacturing process for lutein-zinc gluconate-vitamin A soft capsules includes the following steps: Step 1, flower residue separation and pretreatment: Take the marigold processing by-product flower residue and put it into clean water for flotation to remove impurities such as flower stems and mud, and collect the floating petal components; use a vibrating screen to drain and dehydrate, and control the moisture content of the petals to 72%; send the dehydrated petals into an airflow flash dryer and dry them at 150℃, and then pulverize them to obtain marigold pollen with a moisture content of 7% and a 60% sieve pass rate of 60 mesh.

[0031] Step 2, supercritical carbon dioxide extraction: Marigold pollen is fed into an extraction vessel, and food-grade CO2 is introduced. The extraction is first carried out at a near-critical temperature of 31°C and a pressure of 7.2 MPa for 0.7 h to remove light impurities such as wax and free fatty acids, and the extract at this stage is discarded. Then, the temperature is raised to 48°C and the pressure is raised to 32 MPa for a second stage of extraction for 2.5 h to separate crude lutein oleoresin.

[0032] Step 3, Chelation and Complexation for Demetallization: Dilute crude lutein oleoresin with food-grade n-hexane at a mass ratio of 1:9 and stir to dissolve to obtain a crude resin solution; weigh 1.2% of the crude resin with glucosamine carboxyphosphonic acid complexing agent and prepare a 9% complexing agent aqueous solution; add the complexing agent aqueous solution to the crude resin solution, stir vigorously at 35°C for 40 min, and allow to stand and separate; wash the organic phase twice with an equal volume of deionized water, separate the organic phase, add anhydrous sodium sulfate to dry, filter, and recover n-hexane from the filtrate under reduced pressure at 39°C and a vacuum degree of 0.08 MPa to obtain demetallized lutein oleoresin.

[0033] Step 4, gradient distillation purification: The demetallized lutein oleoresin was fed into a vacuum distillation vessel protected by nitrogen, with a continuous flow of a small amount of high-purity nitrogen. The vacuum was controlled at 0.09 MPa and the material temperature at 45°C. Distillation was carried out for 3.5 hours to remove moisture and low-boiling-point off-flavor components. At this point, the water content of the oleoresin was 1.1%. The oleoresin was then fed into a short-path molecular distillation apparatus, with nitrogen replacement protection throughout the process. The vacuum was controlled at 1 Pa, the evaporation surface temperature at 125°C, and the feed rate at 10 mL / min. Approximately 30% of the light oil components were removed, and the heavy phase components were collected to obtain high-purity lutein oleoresin.

[0034] Step 5, Compounding of active components and preparation of soft capsules: High-purity lutein oleoresin, zinc gluconate, vitamin A acetate, and composite carrier oil are added to the mixing tank at a mass ratio of 1:0.1:0.03:4.5. The composite carrier oil is composed of safflower seed oil, soybean lecithin, and natural vitamin E at a mass ratio of 85:10:5. The mixture is stirred at 38°C under nitrogen protection and low-speed stirring for 30 minutes to form a homogeneous and stable self-emulsifying oil mixture, which is the soft capsule core. The capsule shell gel is prepared by mixing gelatin, glycerin, and purified water at a mass ratio of 1:0.4:1.5, adding 0.1% potassium sorbate by the dry weight of the capsule shell, and degassing the gel before use. The core and capsule shell gel are fed into a rotary pellet press for pressing and molding. After shaping, rotary drying, alcohol washing, and air drying, the finished lutein zinc gluconate vitamin A soft capsules are obtained.

[0035] The finished product tested in this embodiment meets the requirements of GB16740-2014 "National Food Safety Standard for Health Food".

[0036] The preparation method of the glucosamine carboxyphosphonic acid complexing agent is as follows: S1. Dissolve D-glucosamine in deionized water, add phosphorous acid, stir well, and then add concentrated hydrochloric acid. The amount of concentrated hydrochloric acid is 0.8 times the mass of D-glucosamine. Heat to 105℃ and reflux. Slowly add formaldehyde aqueous solution. After the addition is complete, continue to reflux for 5 hours. The mass ratio of D-glucosamine, phosphorous acid, and formaldehyde is 1:0.53:0.18. After the reaction is completed, concentrate under reduced pressure to remove 85% of the water and hydrochloric acid. Dissolve the concentrate in anhydrous methanol, and slowly add acetone while stirring until the system becomes turbid and precipitation is complete. After standing, filter, wash the filter cake with a small amount of cold methanol, and vacuum dry to obtain N-phosphonic acid methylglucosamine solid.

[0037] S2. Dissolve N-phosphonic acid methylglucosamine solid in anhydrous methanol, add triethylamine as an acid-binding agent, and slowly add a methanol solution of tert-butyl bromoacetate dropwise under ice bath cooling, completing the addition within 1 hour; based on the initial D-glucosamine, the mass ratio of D-glucosamine, triethylamine, and tert-butyl bromoacetate is 1:1.5:2.4; after the addition is complete, raise the temperature to room temperature and stir the reaction for 10 hours, filter to remove the generated triethylamine hydrobromide, concentrate the filtrate, and purify it by column chromatography to obtain the glucosamine intermediate.

[0038] S3. Dissolve the glucosamine intermediate in dichloromethane, add trifluoroacetic acid (8 times the mass of the intermediate), stir at room temperature for 6 hours, remove the solvent and excess trifluoroacetic acid by vacuum distillation; dissolve the residue in a small amount of deionized water, adjust the pH to 5.0 with 10 mol / L sodium hydroxide solution, add anhydrous ethanol to precipitate the product, let stand, filter, recrystallize twice with a mixed solvent of ethanol-water (volume ratio 1:1.5), and dry under vacuum at room temperature to obtain the glucosamine carboxyphosphonic acid complexing agent.

[0039] Example 2 A manufacturing process for lutein-zinc gluconate-vitamin A soft capsules includes the following steps: Marigold pollen separation and pretreatment: Marigold processing byproducts, including flower pollen, were placed in clean water for flotation to remove heavy impurities such as flower stems and mud. The floating petal components were collected. The petals were dehydrated by low-pressure pressing using a press to control the moisture content of the petals to 70%. The dehydrated petals were then sent to an airflow flash dryer and dried at 130°C. After drying, the petals were pulverized to obtain marigold pollen with a moisture content of 10% and a 60-mesh sieve pass rate of 53%.

[0040] Supercritical carbon dioxide extraction: Marigold pollen was fed into an extraction vessel and food-grade CO2 was introduced. The extraction was first carried out at a near-critical temperature of 30℃ and a pressure of 7.0MPa for 1 hour to remove light impurities such as wax and free fatty acids, and the extract at this stage was discarded. Then, the temperature was raised to 42℃ and the pressure was raised to 28MPa for a second stage of extraction for 3.5 hours to obtain crude lutein oleoresin.

[0041] Chelating and complexing for demetallization: Crude lutein oleoresin was diluted with food-grade n-hexane at a mass ratio of 1:7 and stirred to dissolve, obtaining a crude resin solution. 0.6% of the crude resin was weighed as a glucosamine carboxyphosphonic acid complexing agent, and a 6% aqueous solution of the complexing agent was prepared. The aqueous solution of the complexing agent was added to the crude resin solution, and the mixture was stirred vigorously at 32°C for 55 min. The mixture was then allowed to stand and the liquid was separated. The organic phase was washed three times with an equal volume of deionized water, and the organic phase was separated. Anhydrous sodium sulfate was added for drying, and the mixture was filtered. The filtrate was subjected to reduced pressure at 36°C and a vacuum of 0.07 MPa to recover n-hexane, yielding demetallized lutein oleoresin.

[0042] Gradient distillation purification: The demetallized lutein oleoresin was fed into a vacuum distillation vessel protected by nitrogen. High-purity nitrogen was purged throughout the process to maintain a slightly positive gauge pressure of 0.01 MPa. Distillation was carried out for 4 hours under vacuum of 0.08 MPa and material temperature of 40°C to remove moisture and low-boiling-point off-flavor components. At this point, the water content of the oleoresin was 1.4%. The oleoresin was then fed into a short-path molecular distillation apparatus under nitrogen purging protection throughout the process. The vacuum was controlled at 0.5 Pa, the evaporation surface temperature at 120°C, and the feed rate at 8 mL / min. Approximately 30% of the light oil components were removed, and the heavy phase components were collected to obtain high-purity lutein oleoresin.

[0043] Compound active ingredient formulation and soft capsule preparation: High-purity lutein oleoresin, zinc gluconate, vitamin A acetate, and composite carrier oil were added to the mixing tank at a mass ratio of 1:0.08:0.02:4. The composite carrier oil was composed of safflower seed oil, soybean lecithin, and natural vitamin E at a mass ratio of 82:12:6. The mixture was stirred at 35°C under nitrogen protection and low speed for 35 minutes to form a homogeneous and stable self-emulsifying oil mixture, which became the soft capsule core. The capsule shell gel was prepared by mixing gelatin, glycerin, and purified water at a mass ratio of 1:0.3:1, adding 0.02% potassium sorbate by dry weight of the capsule shell, and then degassing and reserving the gel. The core and capsule shell gel were fed into a rotary pellet press for molding, followed by shaping, rotary drying, alcohol washing, and air drying to obtain the finished lutein-zinc gluconate-vitamin A soft capsules.

[0044] The preparation method of the glucosamine carboxyphosphonic acid complexing agent is as follows: S1. Dissolve D-glucosamine in deionized water, add phosphorous acid, stir well, and then add concentrated hydrochloric acid. The amount of concentrated hydrochloric acid is 0.6 times the mass of D-glucosamine. Heat to 100℃ and reflux, and slowly add formaldehyde aqueous solution. After the addition is complete, continue to keep the mixture at the reflux temperature for 4 hours. The mass ratio of D-glucosamine, phosphorous acid, and formaldehyde is 1:0.50:0.17. After the reaction is completed, concentrate under reduced pressure to remove 82% of the water and hydrochloric acid. Dissolve the concentrate in anhydrous methanol, and slowly add acetone under stirring until the system becomes turbid and precipitation is complete. After standing, filter, wash the filter cake with a small amount of cold methanol, and dry under vacuum to obtain N-phosphonic acid methylglucosamine solid.

[0045] S2. Dissolve N-phosphonic acid methylglucosamine solid in anhydrous methanol, add triethylamine as an acid-binding agent, and slowly add a methanol solution of tert-butyl bromoacetate dropwise under ice bath cooling, completing the addition within 1 hour; based on the initial D-glucosamine, the mass ratio of D-glucosamine, triethylamine, and tert-butyl bromoacetate is 1:1.2:2.0; after the addition is complete, raise the temperature to room temperature and stir the reaction for 7 hours, filter to remove the generated triethylamine hydrobromide, concentrate the filtrate, and purify it by column chromatography to obtain the glucosamine intermediate.

[0046] S3. Dissolve the glucosamine intermediate in dichloromethane, add trifluoroacetic acid (5 times the mass of the intermediate), stir at room temperature for 4 hours, remove the solvent and excess trifluoroacetic acid by vacuum distillation; dissolve the residue in a small amount of deionized water, adjust the pH to 4.5 with 10 mol / L sodium hydroxide solution, add anhydrous ethanol to precipitate the product, let stand, filter, recrystallize twice with a 1:1 volume ratio of ethanol to water, and dry under vacuum at room temperature to obtain the glucosamine carboxyphosphonic acid complexing agent.

[0047] Example 3 A manufacturing process for lutein-zinc gluconate-vitamin A soft capsules includes the following steps: Step 1, flower residue separation and pretreatment: Take the marigold processing by-product flower residue and put it into clean water for flotation to remove impurities such as flower stems and mud, and collect the floating petal components; use a press to press and dehydrate at low pressure, controlling the moisture content of the petals to 75%; send the dehydrated petals into an airflow flash dryer and dry them at 170℃, then pulverize them to obtain marigold pollen with a moisture content of 4% and a 65% pass rate through a 60-mesh sieve.

[0048] Step 2, supercritical carbon dioxide extraction: Marigold pollen is fed into an extraction vessel, and food-grade CO2 is introduced. First, extraction is carried out for 0.5 hours under near-critical conditions of 32°C and 7.3 MPa to remove light impurities such as wax and free fatty acids, and the extract at this stage is discarded. Then, the temperature is raised to 52°C and the pressure is raised to 38 MPa for a second stage of extraction for 1.5 hours to separate crude lutein oleoresin.

[0049] Step 3, Chelating and Complexing for Demetallization: Dilute crude lutein oleoresin with food-grade n-hexane at a mass ratio of 1:11 and stir to dissolve to obtain a crude resin solution; weigh 2.2% of the crude resin with glucosamine carboxyphosphonic acid complexing agent and prepare a 12% complexing agent aqueous solution; add the complexing agent aqueous solution to the crude resin solution, stir vigorously at 38℃ for 25 min, and let stand to separate the liquid; wash the organic phase twice with an equal volume of deionized water, separate the organic phase, add anhydrous sodium sulfate to dry, filter, and recover n-hexane under reduced pressure at 42℃ and a vacuum degree of 0.09 MPa to obtain demetallized lutein oleoresin.

[0050] Step 4, gradient distillation purification: The demetallized lutein oleoresin was fed into a vacuum distillation vessel protected by nitrogen. High-purity nitrogen was purged throughout the process to maintain a gauge pressure of 0.01 MPa with a slight positive pressure. Distillation was carried out for 3 hours under vacuum conditions of 0.095 MPa and material temperature of 50°C to remove moisture and low-boiling-point off-odor components. At this point, the water content of the oleoresin was 1.0%. The oleoresin was then fed into a short-path molecular distillation apparatus under nitrogen purging protection throughout the process. The vacuum degree was controlled at 2 Pa, the evaporation surface temperature at 130°C, and the feed rate at 12 mL / min. Approximately 30% of the light oil components were removed, and the heavy phase components were collected to obtain high-purity lutein oleoresin.

[0051] Step 5, Compounding of active components and preparation of soft capsules: High-purity lutein oleoresin, zinc gluconate, vitamin A acetate, and composite carrier oil are added to the mixing tank at a mass ratio of 1:0.15:0.05:5. The composite carrier oil is composed of safflower seed oil, soybean lecithin, and natural vitamin E at a mass ratio of 90:6:4. The mixture is stirred at 40℃ under nitrogen protection and low speed for 25 minutes to form a homogeneous and stable self-emulsifying oil mixture, which is the soft capsule core. The capsule shell solution is prepared by mixing gelatin, glycerin, and purified water at a mass ratio of 1:0.6:2, adding 0.2% potassium sorbate by dry weight of the capsule shell, and degassing the mixture before use. The core and capsule shell solution are fed into a rotary pellet press for pressing and molding. After shaping, drying in a rotary drum, washing with alcohol, and air drying, the finished lutein zinc gluconate vitamin A soft capsules are obtained.

[0052] The preparation method of the glucosamine carboxyphosphonic acid complexing agent is as follows: S1. Dissolve D-glucosamine in deionized water, add phosphorous acid, stir well, and then add concentrated hydrochloric acid. The amount of concentrated hydrochloric acid is 1.0 times the mass of D-glucosamine. Heat to 110℃ and reflux, and slowly add formaldehyde aqueous solution. After the addition is complete, continue to reflux for 6 hours. The mass ratio of D-glucosamine, phosphorous acid, and formaldehyde is 1:0.60:0.20. After the reaction is completed, concentrate under reduced pressure to remove 88% of the water and hydrochloric acid. Dissolve the concentrate in anhydrous methanol, and slowly add acetone under stirring until the system becomes turbid and precipitation is complete. After standing, filter, wash the filter cake with a small amount of cold methanol, and vacuum dry to obtain N-phosphonic acid methylglucosamine solid.

[0053] S2. Dissolve N-phosphonic acid methylglucosamine solid in anhydrous methanol, add triethylamine as an acid-binding agent, and slowly add a methanol solution of tert-butyl bromoacetate dropwise under ice bath cooling, completing the addition within 1 hour; based on the initial D-glucosamine, the mass ratio of D-glucosamine, triethylamine, and tert-butyl bromoacetate is 1:1.8:2.8; after the addition is complete, raise the temperature to room temperature and stir the reaction for 13 hours, filter to remove the generated triethylamine hydrobromide, concentrate the filtrate, and purify it by column chromatography to obtain the glucosamine intermediate.

[0054] S3. Dissolve the glucosamine intermediate in dichloromethane, add trifluoroacetic acid (10 times the mass of the intermediate), stir at room temperature for 8 hours, remove the solvent and excess trifluoroacetic acid by vacuum distillation; dissolve the residue in a small amount of deionized water, adjust the pH to 5.5 with 10 mol / L sodium hydroxide solution, add anhydrous ethanol to precipitate the product, let stand, filter, recrystallize twice with a mixed solvent of ethanol-water (volume ratio 1:2), and dry under vacuum at room temperature to obtain the glucosamine carboxyphosphonic acid complexing agent.

[0055] Example 4 A manufacturing process for lutein-zinc gluconate-vitamin A soft capsules includes the following steps: Step 1, flower residue separation and pretreatment: Take the marigold processing by-product flower residue and put it into clean water for flotation to remove impurities such as flower stems and mud, and collect the floating petal components; use a vibrating screen to drain and dehydrate, and control the moisture content of the petals to 72%; send the dehydrated petals into an airflow flash dryer and dry them at 150℃, and then pulverize them to obtain marigold pollen with a moisture content of 7% and a 60% sieve pass rate of 60 mesh.

[0056] Step 2, supercritical carbon dioxide extraction: Marigold pollen is fed into an extraction vessel, and food-grade CO2 is introduced. The extraction is first carried out at a near-critical temperature of 31℃ and a pressure of 7.2MPa for 0.7h to remove light impurities such as wax and free fatty acids, and the extract at this stage is discarded. Then the temperature is raised to 45℃ and the pressure is raised to 30MPa for a second stage of extraction for 2h to obtain crude lutein oleoresin.

[0057] Step 3, Chelation and Complexation for Demetallization: Dilute crude lutein oleoresin with food-grade n-hexane at a mass ratio of 1:9 and stir to dissolve to obtain a crude resin solution; weigh 1.2% of the crude resin with glucosamine carboxyphosphonic acid complexing agent and prepare a 9% complexing agent aqueous solution; add the complexing agent aqueous solution to the crude resin solution, stir vigorously at 35°C for 40 min, and allow to stand and separate; wash the organic phase twice with an equal volume of deionized water, separate the organic phase, add anhydrous sodium sulfate to dry, filter, and recover n-hexane from the filtrate under reduced pressure at 39°C and a vacuum degree of 0.08 MPa to obtain demetallized lutein oleoresin.

[0058] Step 4, gradient distillation purification: The demetallized lutein oleoresin was fed into a vacuum distillation vessel protected by nitrogen. High-purity nitrogen was purged throughout the process to maintain a gauge pressure of 0.01 MPa with a slight positive pressure. Distillation was carried out for 3.5 hours under vacuum conditions of 0.09 MPa and material temperature of 45°C to remove moisture and low-boiling-point off-odor components. At this point, the water content of the oleoresin was 1.3%. The oleoresin was then fed into a short-path molecular distillation apparatus under nitrogen purging protection throughout the process. The vacuum degree was controlled at 1 Pa, the evaporation surface temperature at 125°C, and the feed rate at 10 mL / min. Approximately 30% of the light oil components were removed, and the heavy phase components were collected to obtain high-purity lutein oleoresin.

[0059] Step 5, Compounding of active components and preparation of soft capsules: High-purity lutein oleoresin, zinc gluconate, vitamin A acetate, and composite carrier oil are added to the mixing tank at a mass ratio of 1:0.12:0.04:4.2. The composite carrier oil is composed of safflower seed oil, soybean lecithin, and natural vitamin E at a mass ratio of 88:8:4. The mixture is stirred at 38°C under nitrogen protection and low-speed stirring for 30 minutes to form a homogeneous and stable self-emulsifying oil mixture, which is the soft capsule core. The capsule shell gel solution is prepared by mixing gelatin, glycerin, and purified water at a mass ratio of 1:0.4:1.5, adding 0.1% potassium sorbate by the dry weight of the capsule shell, and then degassing and preparing for use. The core and capsule shell gel solution are fed into a rotary pellet press for pressing and molding. After shaping, rotary drying, alcohol washing, and air drying, the finished lutein zinc gluconate vitamin A soft capsules are obtained.

[0060] The preparation method of the glucosamine carboxyphosphonic acid complexing agent is as follows: S1. Dissolve D-glucosamine in deionized water, add phosphorous acid, stir well, and then add concentrated hydrochloric acid. The amount of concentrated hydrochloric acid is 0.8 times the mass of D-glucosamine. Heat to 105℃ and reflux. Slowly add formaldehyde aqueous solution. After the addition is complete, continue to reflux for 5 hours. The mass ratio of D-glucosamine, phosphorous acid, and formaldehyde is 1:0.53:0.18. After the reaction is completed, concentrate under reduced pressure to remove 85% of the water and hydrochloric acid. Dissolve the concentrate in anhydrous methanol, and slowly add acetone while stirring until the system becomes turbid and precipitation is complete. After standing, filter, wash the filter cake with a small amount of cold methanol, and vacuum dry to obtain N-phosphonic acid methylglucosamine solid.

[0061] S2. Dissolve N-phosphonic acid methylglucosamine solid in anhydrous methanol, add triethylamine as an acid-binding agent, and slowly add a methanol solution of tert-butyl bromoacetate dropwise under ice bath cooling, completing the addition within 1 hour; based on the initial D-glucosamine, the mass ratio of D-glucosamine, triethylamine, and tert-butyl bromoacetate is 1:1.5:2.4; after the addition is complete, raise the temperature to room temperature and stir the reaction for 10 hours, filter to remove the generated triethylamine hydrobromide, concentrate the filtrate, and purify it by column chromatography to obtain the glucosamine intermediate.

[0062] S3. Dissolve the glucosamine intermediate in dichloromethane, add trifluoroacetic acid (8 times the mass of the intermediate), stir at room temperature for 6 hours, remove the solvent and excess trifluoroacetic acid by vacuum distillation; dissolve the residue in a small amount of deionized water, adjust the pH to 5.0 with 10 mol / L sodium hydroxide solution, add anhydrous ethanol to precipitate the product, let stand, filter, recrystallize twice with a mixed solvent of ethanol-water (volume ratio 1:1.5), and dry under vacuum at room temperature to obtain the glucosamine carboxyphosphonic acid complexing agent.

[0063] Comparative Example 1 The preparation process is the same as in Example 1, except that the chelation, complexation and demetallization process in step 3 is omitted, and the crude lutein oleoresin directly enters the gradient distillation purification step.

[0064] Comparative Example 2 The preparation process is the same as in Example 1, except that in step 5, ordinary soybean oil is used instead of the composite carrier oil, and soybean phospholipids and natural vitamin E are not added.

[0065] Comparative Example 3 The preparation process is the same as in Example 1, except that: step 2 adopts traditional single-stage supercritical extraction, which is directly extracted at 48℃ and 32MPa for 3.2h without performing the first-stage near-critical impurity removal; and the metal removal process in step 3 is omitted. In step 5, ordinary soybean oil is used as a carrier and zinc gluconate and vitamin A acetate are not added.

[0066] Experimental performance testing The soft capsules prepared in Example 1 and Comparative Examples 1-3 were subjected to performance testing. The performance indicators and test methods are shown in Table 1 below:

[0067] The test results are shown in Table 2 below:

[0068] The test results from the examples and comparative examples show that: (1) The lutein purity of Example 1 was significantly higher than that of Comparative Example 3, indicating that the process combination of segmented supercritical extraction and gradient distillation purification can effectively remove wax, free fatty acids and light oil impurities, significantly improve product purity, and the effect is far superior to the traditional single-stage extraction process.

[0069] (2) Comparing Example 1 and Comparative Example 1, it can be seen that the chelation complexation demetallization process can remove Fe 3+ Cu 2+ The residual amount is reduced by more than an order of magnitude, Fe 3+ The removal rate exceeded 96%; the corresponding accelerated storage retention rate increased from 56.2% to 93.1%, proving that transition metal ions are the core factor catalyzing the oxidative degradation of lutein. The specific demetallization of the glucosamine carboxyphosphonic acid complexing agent of this invention is a key technology for improving product stability.

[0070] (3) Comparing Example 1 and Comparative Example 2, it can be seen that under the premise of similar metal residue levels, the product using composite carrier oil has a 17% higher accelerated retention rate than ordinary soybean oil carrier. This indicates that the compound system of safflower seed oil, soybean phospholipids and natural vitamin E can synergistically play an antioxidant and dispersion stabilizing role, forming a double protective barrier with the metal removal process, and further enhancing product stability.

[0071] (4) The product prepared by the traditional process in Comparative Example 3 has low purity, high metal residue and poor stability. However, the present invention achieves a significant improvement in product purity and storage stability through the synergistic combination of multiple processes such as pretreatment, segmented extraction, chelation demetallization, gradient distillation and compounding. The various technical features are not simply the sum of effects, but have produced a significant synergistic effect. At the same time, the compounding of zinc gluconate and vitamin A expands the eye protection function of the product and has higher market value.

[0072] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. The illustrative expressions of the above terms in this specification should not be construed as necessarily referring to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can combine and integrate the different embodiments or examples described in this specification.

[0073] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A process for the production of a soft capsule of lutein zinc gluconate vitamin A, characterized in that, Includes the following steps: Step 1: After removing impurities by flotation, marigold flowers are dried and pulverized to obtain marigold flower powder; Step 2: Supercritical CO2 stepwise extraction is performed on marigold pollen. First, wax and free fatty acids are extracted under near-critical conditions, and then the temperature and pressure are increased to extract crude lutein oleoresin. Step 3: Dilute the crude oleoresin with an organic solvent, then contact it with a glucosamine carboxyphosphonic acid complexing agent for demetallization treatment, and recover the solvent to obtain the demetallized crude oleoresin. Step 4: Under an inert atmosphere, the crude demetallized oleoresin is first vacuum distilled to remove water and low-boiling-point substances, and then light oils are removed by molecular distillation. The heavy phase is collected to obtain high-purity lutein oleoresin. Step 5: Mix high-purity lutein oleoresin with zinc gluconate, vitamin A acetate, and composite carrier oil, homogenize to form the inner core, then press the core into capsules using capsule shell glue, and dry to obtain lutein zinc gluconate vitamin A soft capsules.

2. The process for the production of lutein zinc gluconate vitamin A softgel capsule as claimed in claim 1 wherein, The stepwise extraction described in step 2 is as follows: first, extract at a temperature of 30-32℃ and a pressure of 7.0-7.3MPa for 0.5-1h, and then separate and discard the extract; then extract at a temperature of 42-52℃ and a pressure of 28-38MPa for 1.5-3.5h.

3. The process for the production of lutein zinc gluconate vitamin A softgel capsule as claimed in claim 1 wherein, The demetallization process described in step 3 is a liquid-liquid chelate extraction: the crude oleoresin is diluted with food-grade n-hexane, and then an aqueous solution of the glucosamine carboxyphosphonic acid complexing agent is added and stirred to react. After standing and separating the liquids, the organic phase is washed with water, dried, and concentrated to obtain the demetallized crude oleoresin.

4. The process for the production of lutein zinc gluconate vitamin A soft capsules as claimed in claim 1 wherein, The preparation method of the glucosamine carboxyphosphonic acid complexing agent includes: S1. Dissolve D-glucosamine in deionized water, add phosphorous acid, stir well, add concentrated hydrochloric acid, heat to reflux, add formaldehyde aqueous solution dropwise, and after the addition is complete, keep the mixture at reflux for 4-6 hours; after the reaction is complete, concentrate under reduced pressure, precipitate, filter, wash, and vacuum dry to obtain N-phosphonic acid methylglucosamine solid. S2. Dissolve N-phosphonic acid methyl glucosamine solid in anhydrous methanol, add triethylamine, and add a methanol solution of tert-butyl bromoacetate dropwise under ice bath. After the addition is complete, raise the temperature to room temperature and stir the reaction for 7-13 hours. Filter, concentrate the filtrate, and purify by column chromatography to obtain the glucosamine intermediate. S3. Dissolve the glucosamine intermediate in dichloromethane, add trifluoroacetic acid (5-10 times the mass of the intermediate), stir at room temperature for 4-8 hours, remove the solvent and trifluoroacetic acid by vacuum evaporation; dissolve the residue in water, adjust the pH to 4.5-5.5, precipitate, filter, recrystallize, and vacuum dry to obtain the glucosamine carboxyphosphonic acid complexing agent.

5. The process for the production of lutein zinc gluconate vitamin A softgel capsule as claimed in claim 4 wherein, In S1, the mass ratio of D-glucosamine, phosphorous acid, and formaldehyde is 1:0.50-0.60:0.17-0.20; in S2, based on D-glucosamine, the mass ratio of D-glucosamine, triethylamine, and tert-butyl bromoacetate is 1:1.2-1.8:2.0-2.

8.

6. The process for the production of lutein zinc gluconate vitamin A softgel capsule as claimed in claim 4 wherein, In S3, the amount of trifluoroacetic acid used is 5-10 times the mass of the intermediate, and the volume ratio of the ethanol-water mixed solvent used for recrystallization is 1:1-2.

7. The production process of the lutein-zinc gluconate-vitamin A soft capsules according to claim 1, characterized in that, In step 4, the vacuum distillation conditions are: slightly positive nitrogen pressure, vacuum degree 0.08-0.095 MPa, material temperature 40-50℃, and distillation time 3-4 h; the molecular distillation conditions are: vacuum degree 0.5-2 Pa, evaporation surface temperature 120-130℃, and feed rate 8-12 mL / min.

8. The production process of lutein-zinc gluconate-vitamin A soft capsules according to claim 1, characterized in that, The composite carrier oil in step 5 is composed of safflower seed oil, soybean lecithin, and natural vitamin E in a mass ratio of 82-90:6-12:2-6; the mass ratio of high-purity lutein oleoresin, zinc gluconate, vitamin A acetate, and composite carrier oil in the inner core is 1:0.08-0.15:0.02-0.05:4-5.

9. The production process of lutein-zinc gluconate-vitamin A soft capsules according to claim 1, characterized in that, The capsule shell solution described in step 5 is prepared by mixing gelatin, glycerin, and purified water in a mass ratio of 1:0.3-0.6:1-2, and adding 0.02%-0.2% potassium sorbate based on the dry weight of the capsule shell.

10. A lutein-zinc gluconate-vitamin A soft capsule, characterized in that, It was prepared using the preparation method described in claim 1.

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