WO2022021975A9 - 一种稳定、高生物利用度的类胡萝卜素微胶囊及其制备方法 - Google Patents

一种稳定、高生物利用度的类胡萝卜素微胶囊及其制备方法 Download PDF

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WO2022021975A9
WO2022021975A9 PCT/CN2021/090793 CN2021090793W WO2022021975A9 WO 2022021975 A9 WO2022021975 A9 WO 2022021975A9 CN 2021090793 W CN2021090793 W CN 2021090793W WO 2022021975 A9 WO2022021975 A9 WO 2022021975A9
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carotenoid
oil
organic solvent
solution
microcapsules according
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PCT/CN2021/090793
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English (en)
French (fr)
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WO2022021975A1 (zh
Inventor
李建东
陈志荣
石立芳
黄国东
潘丽爽
尹红
仇丹
张其磊
朱小勇
刘香
戚丽丹
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浙江新和成股份有限公司
浙江大学
新昌新和成维生素有限公司
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Priority to US17/793,937 priority Critical patent/US20230063291A1/en
Priority to DE112021000453.0T priority patent/DE112021000453T5/de
Publication of WO2022021975A1 publication Critical patent/WO2022021975A1/zh
Publication of WO2022021975A9 publication Critical patent/WO2022021975A9/zh

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/105—Aliphatic or alicyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/179—Colouring agents, e.g. pigmenting or dyeing agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
    • A23D9/00—Other edible oils or fats, e.g. shortenings, cooking oils
    • A23D9/007—Other edible oils or fats, e.g. shortenings, cooking oils characterised by ingredients other than fatty acid triglycerides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
    • A23D9/00—Other edible oils or fats, e.g. shortenings, cooking oils
    • A23D9/02—Other edible oils or fats, e.g. shortenings, cooking oils characterised by the production or working-up
    • A23D9/04—Working-up
    • A23D9/05—Forming free-flowing pieces
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/111—Aromatic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A23K20/147—Polymeric derivatives, e.g. peptides or proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/158—Fatty acids; Fats; Products containing oils or fats
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/163—Sugars; Polysaccharides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/174—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/80—Feeding-stuffs specially adapted for particular animals for aquatic animals, e.g. fish, crustaceans or molluscs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present application relates to the field of medicine and chemical industry, in particular to a stable, high bioavailability carotenoid microcapsule and a preparation method thereof.
  • Carotenoids are a class of polyene compounds with multiple unsaturated bonds. As one of the most important natural pigments, they have a wide range of biological activities, including pro-vitamin A, antioxidant functions, anti-tumor, eye protection and heart disease prevention. Vascular diseases, prevention of osteoporosis, promotion of weight loss, and skin protection have attracted more and more attention from researchers in the fields of medicine, food, feed, aquaculture, and cosmetics.
  • carotenoids Since most carotenoids are insoluble in water and have little solubility in vegetable oils, they are easily affected by chemical substances, machinery, light, oxygen, heat, etc. and become highly unstable during food processing and storage. their application in functional foods. In addition, as micronutrients, the physiological efficacy of carotenoids mainly depends on their bioavailability in the body. A large number of studies have shown that the existence form and particle size of carotenoids have a great influence on their bioavailability.
  • Carotenoid particles The smaller the particle size, the easier it is to be absorbed and utilized by the organism after being ingested, that is, it has a higher bioavailability, so people always try to reduce the particle size of carotenoid, so that it can reach the micron or even nanoscale, Therefore, the current focus of carotenoid development and research is to select formulations with fine particles, good stability and high bioavailability as the intake carrier of carotenoids.
  • CN101828693A obtains a carotenoid oil suspension with a particle size of about 10 ⁇ m by treating the crude crystals of carotenoids with tetrahydrofuran, ethanol, vegetable oil, etc.; CN102552173B uses the process of atomizing the carotenoid solution into vegetable oil to obtain an average particle size of less than 5 ⁇ m
  • the uniformity and particle size of carotenoids in both processes could not reach the level of emulsions.
  • carotenoids have poor chemical stability in oil solutions, and are prone to side reactions.
  • the application of oil suspension formulations in the feed, food and health care products industries is not convenient.
  • CN108030063A uses ⁇ -carotene, monoglyceride, triglyceride and vitamin E as the oil phase, passes through a coil heat exchanger heated by an oil bath at 140-250 °C, and after the ⁇ -carotene in the oil suspension is completely melted, add The wall material solution is emulsified, supplemented with a digestion enhancer, and spray-dried to obtain beta-carotene microcapsules.
  • the high-temperature melting method easily leads to the degradation or isomerization of nutrients at high temperature, reducing their biological activity.
  • US3998753 describes a method for preparing water-dispersible carotenoids, wherein the particle size of carotenoids is less than 1 ⁇ m.
  • the method is to first prepare a solution of carotenoids and other additives into an organic solvent, and then add them to a solution containing gelatin, dispersant , in the aqueous solution of the stabilizer, the system is formed into an emulsion through high-speed shearing; the organic solvent is removed, and the desired powder is obtained by spray drying;
  • the method for preparing the water-dispersed carotenoid powder described in US4522743 is to mix the carotenoid in 50 ⁇ 50 ⁇ Dissolved in a volatile water-miscible solvent at 200°C within 10 seconds, and then rapidly mixed with an aqueous solution containing protective colloids at 0°C to 50°C, carotenoids are dispersed in protective colloids with a size of ⁇ 0.5 ⁇ m.
  • CN107669657A adopts the method of dissolving carotenoids in an organic solvent to form an oil phase, and emulsified with an aqueous phase formed by dissolving an emulsion stabilizer and water, then heating the emulsion to remove the solvent, then adding a coating wall material to homogenize, and granulating Drying to prepare more stable carotenoid dry powder or microparticles.
  • US6936279B2 discloses a method for preparing carotenoid oil suspension, wherein carotenoids are first mixed with a certain water-insoluble solvent, then mixed with vegetable oil, and then atomized under the action of nitrogen flow, and the atomized solution is collected and recovered. Wherein the solvent, the carotenoid oil suspension is obtained.
  • ester solvent the obtained solution is added to high-speed stirring ethanol or isopropanol in the form of spray, so that carotenoids are precipitated in the form of amorphous powder ⁇ 2 ⁇ m; Carotene, the filter cake is washed with ethanol or isopropanol, and filtered to dry; then the filter cake is added to the aqueous solution containing the protective colloid, first stirred and beaten, then homogeneously emulsified, and then the residual solvent is removed to make an aqueous dispersion Finally, the dispersion is granulated by spray method, and then fluidized and dried to obtain the preparation of water-dispersible carotenoid.
  • the process innovation is carried out by the dual-solvent method, which greatly shortens the precipitation time, but the carotenoid particle size needs to be further refined, and the bioavailability needs to be further improved.
  • the present application hopes to find an efficient and simple method, which can quickly remove the organic solvent, and the obtained carotenoid preparation has fine particles and good embedding effect. Good, stable and bioavailable products.
  • the technical problem to be solved in the present application is to provide a carotenoid microcapsule with fine particle size, high bioavailability and good stability and a preparation method thereof in view of the current state of the prior art.
  • a kind of preparation method of stable, high bioavailability carotenoid microcapsules, described method comprises the steps:
  • the dispersing system in step b) includes a dispersing device, a container connected to the dispersing device, a conveying device and a heating device, and the dispersing device is used for the carotenoid solution and thermal grease obtained in step a). contact with the circulating material, so that the carotenoid is fully dispersed in the hot grease; the conveying device is used to transport the material in the dispersing system; the heating device is used to heat the grease or the circulating material into a liquid state .
  • the dispersing device includes a contact section, a constriction section and an expansion section connected in sequence;
  • the contact section is provided with an injection port and an atomization port, and the injection port introduces the heated liquid hot grease or circulating material into the contact section through the injection port; the atomization port injects the carrotoid obtained in step a).
  • the carotenoid solution forms tiny mist droplets through the atomization port, which are introduced into the contact section, contact and mix with the jet-like liquid hot grease or circulating material, and vaporize the organic solvent in the carotenoid solution to form carotenoid. prime particles and dispersed in the thermal grease;
  • the shrinking section further mixes the carotenoid droplets formed in the contacting section with grease, evaporates the organic solvent, enters the expanding section, and then enters the container connected to the dispersing device.
  • the container connected to the dispersing device further comprises a vacuum port, and the vaporized organic solvent is discharged from the container through the vacuum port.
  • the dispersion system is operated continuously or batchwise.
  • the residence time of the material in the dispersion system is ⁇ 20h, optionally ⁇ 10h.
  • the temperature of the thermal grease is 60°C-100°C.
  • step b) only part of the organic solvent in the carotenoid solution is vaporized and removed, optionally, the residual organic solvent in the carotenoid mixed dispersion liquid is The content is lower than 1%, optionally lower than 0.5%, optionally lower than 0.2%.
  • step c) further includes the step of removing the residual organic solvent in the emulsion after emulsification.
  • the carotenoid is present in the mixed dispersion liquid of carotenoid obtained in step b) in a state of partial dissolution and particle dispersion.
  • the average particle size of the carotenoid particles in the carotenoid mixed dispersion liquid is 0.05 ⁇ m-0.2 ⁇ m.
  • the mass ratio of the thermal grease to the carotenoid crystals is 0.7:1-20:1, optionally 1:1-10:1.
  • the emulsification method described in step c) is one or more of high pressure homogeneous emulsification, in-line pipeline high shear emulsification, supergravity emulsification and static mixing.
  • the protective colloid is selected from gelatin, starch octenyl succinate, gum arabic, sodium lignosulfonate, calcium lignosulfonate, sodium polyacrylate and sodium carboxymethylcellulose one or more of.
  • the mixed dispersion is dispersed in the protective colloid, the average particle size of the dispersed phase is less than 0.7 ⁇ m, and the dispersed phase contains at least one carotenoid particle , at least one oil in which the carotenoid particles are encapsulated in a nano-dispersed form.
  • the organic solvent of step a) is selected from one or more of chloroform, dichloromethane, ethyl acetate, propyl acetate, acetone and propanol.
  • the mass ratio of the organic solvent to the carotenoid crystal in step a) is 100:1-2000:1.
  • antioxidants are added to the carotenoid solution, and the antioxidants are selected from TBHQ, VC-palmitate, tocopherol, rosemary, tea polyphenols, propyl gallate, BHT , one or more of sodium ascorbate, ascorbic acid and ethoxyquin; and/or, the mass ratio of the antioxidant to the carotenoid crystal is 0.1:1-3:1.
  • the hot oil in the step b) is a physiologically acceptable oil, and the oil is selected from one or more of waxes, vegetable oil and hydrogenated vegetable oil.
  • the waxes are selected from the group consisting of beeswax, carnauba wax, candelilla wax, microcrystalline wax, montanate wax, rice sprout oil wax, spermaceti, lanolin wax, simender wax, One or more of Sasol wax and Japanese wax, optionally beeswax; and/or, the vegetable oil is selected from corn oil, soybean oil, sunflower oil, olive oil, coconut oil, rapeseed oil, cottonseed one or more of oil, palm oil, palm stearin and cocoa butter; and/or, the hydrogenated vegetable oil is selected from one or more of hydrogenated cottonseed oil, hydrogenated palm oil and hydrogenated soybean oil.
  • the carotenoid crystals of step a) are selected from beta-carotene, lutein, zeaxanthin, lycopene, canthaxanthin, astaxanthin, capsanthin, tartrazine One or more of ⁇ -apo-8'-carotene aldehyde and ⁇ -apo-8'-carotene acid ethyl ester.
  • a stable and highly bioavailable carotenoid microcapsule obtained by the preparation method of the carotenoid microcapsule, wherein the dispersed phase of the carotenoid microcapsule is dispersed in the protective colloid, and the average particle size of the dispersed phase is ⁇ 0.7 ⁇ m, the dispersed phase contains at least one carotenoid particle and at least one oil, and the carotenoid particle is encapsulated in the oil in a nano-dispersed form.
  • the carotenoid crystals are pre-dissolved in an organic solvent containing an antioxidant to obtain a carotenoid solution, and a dispersion system is used to make the carotenoid solution form tiny mist droplets through the atomization port, and spray
  • a dispersion system is used to make the carotenoid solution form tiny mist droplets through the atomization port, and spray
  • the hot grease or circulating material in the state of contact, the hot grease or circulating material introduced from the injection port generates negative pressure, and the temperature is higher than the boiling point of the organic solvent, and the organic solvent is rapidly vaporized during the contact process with the droplets formed by the carotenoid solution.
  • carotenoid particles are formed and dispersed in the oil, the carotenoids in the solution are precipitated and grown in a molecular state, because the residual solvent and hot oil in the mixed dispersion system still have a certain solubility for carotenoids, resulting in carotenoids.
  • the precipitation of the carotenoid is obviously inhibited, and the particle size can be controlled at the nanoscale under the condition of high-speed mixing; further, when the material formed in the contact section of the dispersing device enters the shrinking section, the carotenoid solution droplets are further mixed with the oil, so that the The organic solvent in the droplets is evaporated to obtain a mixed dispersion of carotenoids.
  • the carotenoid in the carotenoid dispersion formed by the present application can reach the level of fine particles.
  • the obtained mixed dispersion is mixed and emulsified with an aqueous solution of protective colloid, and the remaining solvent is removed, and then granulated and molded.
  • the carotenoid particles in the microcapsules are encapsulated in the oil in the form of nano-dispersion.
  • the presence of oil can provide dense protection for the carotenoid particles in the microcapsules, isolate the oxygen, and make the product have better processing stability.
  • the microcapsules of the present application After the microcapsules of the present application are ingested into the animal body, in the strongly acidic gastric juice environment, the presence of oil isolates the destructive effect of gastric acid on carotenoids, so that the product has better chemical stability.
  • the product After being decomposed in the small intestine, it is emulsified by bile together with other lipids to form micelles, which freely diffuse into the intestinal mucosal cells.
  • Carotenoid particles have small particle size, and are more easily emulsified by bile together with lipids in the feed when encased in oil, and form micelles more effectively to be absorbed by animals, and the product has high bioavailability.
  • the carotenoid particles in the microcapsules of the present application are encapsulated in the oil in a nano-dispersed form, and the presence of the oil can provide dense protection for the carotenoid particles therein, isolate oxygen, and make the product have better processing stability .
  • the carotenoid particles in the microcapsules of the present application are small in particle size, and are more easily emulsified by bile together with lipid substances in the feed when encased in oil, and form micelles more effectively to be absorbed by animals, and the bioavailability of the product is high.
  • FIG. 1 is a schematic flowchart of a method for preparing carotenoid microcapsules according to an embodiment of the application.
  • FIG. 2 is a schematic structural diagram of a dispersion system according to an embodiment of the application, wherein 1—dispersing device; 2—container; 3—conveying device; 4—heating device.
  • FIG. 3 is a schematic diagram of a dispersing device according to an embodiment of the application, wherein 5—spray port; 6—atomization port; 7—contact section; 8—contraction section;
  • FIG. 4 is a schematic structural diagram of a carotenoid microcapsule according to an embodiment of the present application.
  • the application provides a kind of preparation method of carotenoid microcapsules, comprises the following steps:
  • the obtained carotenoid mixed dispersion is mixed with the aqueous solution of the protective colloid, and emulsified to obtain an emulsion;
  • the raw materials used eg, organic solvents, oils and fats, etc.
  • the raw materials used are all physiologically acceptable substances.
  • the term "at least a majority” refers to greater than 50%, optionally > 60%, > 70%, > 80%, > 90%, > 95%, > 96%, > 97%, > 98% or > 99%.
  • the application uses hot oil to disperse carotenoids, and the hot oil and some organic solvents in the mixed dispersion system still have a certain solubility for carotenoids, resulting in the precipitation of carotenoids being significantly inhibited.
  • the particle size of carotenoids can be controlled at the nanoscale.
  • the presence of oil can also provide dense protection for the carotenoid particles in it, isolate oxygen and gastric acid, and make the product have better processing stability and chemical stability.
  • the particle size of the carotenoid particles in the carotenoid microcapsules obtained in the present application is controlled to be smaller, and the carotenoid particles are wrapped in oil and are more likely to be mixed with the lipid substances in the feed. At the same time, it is emulsified by bile to form micelles more effectively to be absorbed by animals, and the product has high bioavailability.
  • the carotenoid crystals of step a) are selected from beta-carotene, lutein, zeaxanthin, lycopene, canthaxanthin, astaxanthin, capsanthin, tartrazine , one or more of ⁇ -apo-8'-carotene aldehyde and ⁇ -apo-8'-carotene acid ethyl ester.
  • the organic solvent of step a) can be selected from one or more of chloroform, dichloromethane, ethyl acetate, propyl acetate, acetone and propanol.
  • the mass ratio of the organic solvent to the carotenoid crystal in step a) is 100:1-2000:1.
  • the mass ratio of the organic solvent to the carotenoid crystal can be 100:1-500:1, 500:1-800:1, 800:1-1000:1, 1000:1-1200:1, 1200:1 -1400:1, 1400:1-1700:1 or 1700:1-2000:1.
  • antioxidants are added to the carotenoid solution, and the antioxidants are selected from TBHQ, VC-palmitate, tocopherol, rosemary, tea polyphenols, propyl gallate, BHT, One or more of sodium ascorbate, ascorbic acid and ethoxyquin.
  • the mass ratio of the antioxidant to the carotenoid crystal is 0.1:1-3:1.
  • the carotene crystals can be completely dissolved in the organic solvent by heating.
  • the thermal grease in the step b) is a physiologically acceptable grease
  • the grease is selected from one or more of waxes, vegetable oils and hydrogenated vegetable oils.
  • the waxes are selected from beeswax, carnauba wax, candelilla wax, microcrystalline wax, montanate wax, rice sprout oil wax, spermaceti, lanolin wax, simender wax, One or more of Sol wax and Japanese wax, optionally beeswax.
  • the vegetable oil is selected from one or more of corn oil, soybean oil, sunflower oil, olive oil, coconut oil, rapeseed oil, cottonseed oil, palm oil, palm stearin and cocoa butter kind.
  • the hydrogenated vegetable oil is selected from one or more of hydrogenated cottonseed oil, hydrogenated palm oil and hydrogenated soybean oil.
  • the temperature of the thermal grease is 60°C-100°C. Specifically, it can be 60°C-70°C, 70°C-80°C, 80°C-90°C, or 90°C-100°C.
  • the dispersing system in step b) includes a dispersing device 1, a container 2 connected to the dispersing device 1, a conveying device 3 and a heating device 4.
  • the dispersing device 1 uses The carotenoid solution obtained in step a) contacts with hot grease or circulating material, so that carotenoids are fully dispersed in the grease; the conveying device 3 is used for system material transportation; the heating device 4 is used for heating grease or circulating material The material makes it liquid.
  • the dispersing system is a circulating transmission system, that is, the materials in the dispersing device can enter the container, and the materials in the container can be circulated back into the dispersing device.
  • the circulating material refers to the components of the carotenoid solution that are transported in the dispersing system again after the organic solvent has been removed by the dispersing device one or more times.
  • the dispersing device 1 includes a contact section 7, a constriction section 8 and an expansion section 9 connected in sequence, the contact section 7 is provided with a spray port 5 and an atomization port 6, and the spray port 5 will heat
  • the liquid hot grease or circulating material is introduced into the contact section 7 through the injection port 5; the carotenoid solution obtained in the step a) is formed into tiny droplets through the atomization port 6 by the atomization port 6, and is introduced into the contact section 7, and the carotenoid solution obtained in the step a) is formed into a tiny droplet.
  • the spray-like liquid hot grease or circulating materials are contacted and mixed to vaporize the organic solvent in the carotenoid solution to form carotenoid particles and disperse in the grease.
  • the shrinking section 8 further mixes the carotenoid droplets formed by the contacting section 7 with grease, quickly evaporates the organic solvent, enters the expanding section 9, and then enters the container 2 connected to the dispersing device 1.
  • the container 2 of the dispersing device 1 further includes a vacuum port, and the vaporized organic solvent is discharged from the container 2 through the vacuum port.
  • the dispersion system is a continuous operation or a batch operation.
  • Continuous operation means that the carotenoid solution continuously enters the dispersing system for processing, for example, the carotenoid solution continuously enters the dispersing system at a predetermined speed, as shown in Example 7.
  • Intermittent operation refers to feeding the carotenoids into the dispersion system at one time, and the materials that have been reacted in the dispersion system undergo subsequent steps to obtain an emulsion and granulate to obtain carotenoid microcapsules, as shown in Example 1. Show.
  • the residence time of the material in the dispersion system is ⁇ 20h, optionally ⁇ 10h.
  • step b) the hot grease or circulating material enters the contact section 7 of the dispersing device 1 through the jet port 5 , and the carotenoid solution is atomized by the dispersing device 1 with the carotenoid solution.
  • the vaporized organic solvent is discharged through the vacuum port above the container 2 to obtain a mixed dispersion of carotenoids, which is circulated through the conveying device 3, and the dispersion is to be mixed.
  • the medium carotenoid particles reach 0.05 ⁇ m-0.2 ⁇ m, the material is discharged to perform step c).
  • step b) removes at least most of the organic solvent in the carotenoid solution.
  • step b) only part of the organic solvent in the carotenoid solution is evaporated and removed, and the residual organic solvent can be removed after emulsification.
  • Part of the organic solvent and hot oil in the mixed dispersion still have a certain solubility for carotenoids, which leads to the obvious inhibition of the precipitation of carotenoids.
  • the particle size can be controlled in nano-scale.
  • the mass percentage of the organic solvent removed in step b) is greater than 99%.
  • the carotenoid solution is sprayed and contacted with the hot grease, and part of the organic solvent is removed under a negative pressure system. The specific removal time is determined according to the actual solvent amount, removal ratio requirements and actual system conditions.
  • step c) further includes: after emulsification, the step of removing the residual organic solvent in the emulsion is performed.
  • a specific desolvation method can be a conventional method, such as vacuum desolvation. The specific removal time is determined according to the actual remaining solvent amount and the actual system conditions.
  • the carotenoids are present in the mixed dispersion liquid of carotenoids obtained in step b) in a state of partial dissolution and particle dispersion.
  • at least most of the carotenoids are present in the mixed dispersion of carotenoids in the state of particle dispersion, that is, most of the carotenoids are dispersed in the form of particles, and a small part is dissolved in the mixed dispersion of carotenoids.
  • >80% of the mixture is present in the carotenoid mixed dispersion in a state of particle dispersion.
  • the average particle size of the carotenoid particles in the carotenoid mixed dispersion liquid is 0.05 ⁇ m-0.2 ⁇ m.
  • the particle size of the carotenoid particles may be 0.05 ⁇ m-0.1 ⁇ m, 0.1 ⁇ m-0.15 ⁇ m or 0.15 ⁇ m-0.2 ⁇ m.
  • the mass ratio of the hot oil and carotenoid crystals is (0.7-20):1.
  • the mass ratio of hot oil and carotenoid crystals can be 0.7:1-1:1, 1:1-5:1, 5:1-10:1, 10:1-15:1, 15:1 -20:1.
  • the emulsification method described in step c) is one or more of high pressure homogeneous emulsification, in-line pipeline high shear emulsification, supergravity emulsification and static mixing.
  • the emulsification method may be high pressure homogeneous emulsification.
  • the protective colloid can be selected from gelatin, starch octenyl succinate, gum arabic, sodium lignosulfonate, calcium lignosulfonate, sodium polyacrylate and sodium carboxymethylcellulose one or more of.
  • the carotenoid crystals are pre-dissolved in an organic solvent containing an antioxidant to obtain a carotenoid solution, which is then atomized into mist droplets through the dispersion system, and contacted with the hot grease in a sprayed state.
  • the organic solvent in the carotenoid solution evaporates rapidly, so that the carotenoids in the solution are precipitated and grown in a molecular state. Because the residual solvent and hot oil in the mixed dispersion system still have a certain solubility for carotenoids, resulting in The precipitation of carotenoids is significantly inhibited.
  • the particle size can be controlled at nano-scale; and compared with the traditional preparation method (the carotenoid solution is emulsified under the action of water-soluble colloids and desolubilized at atmospheric pressure) , the organic solvent of the present application is removed online, which can greatly simplify the operation steps.
  • the obtained mixed dispersion is mixed and emulsified with the aqueous solution of protective colloid, and the remaining solvent is removed, and then granulated and formed.
  • the presence of oil in the product also provides dense protection for the carotenoid particles in it.
  • the mixed dispersion is dispersed in the protective colloid, the average particle size of the dispersed phase is less than 0.7 ⁇ m, and the dispersed phase comprises at least one carotenoid particle, At least one oil in which the carotenoid particles are encapsulated in a nano-dispersed form.
  • the spray granulation in step d) is carried out in the presence of a coating material.
  • the coating material is selected from corn starch, silicon dioxide, tricalcium phosphate and mixtures thereof.
  • the drying method of step d) may be fluidized bed drying.
  • the emulsion is fed into a spray granulation tower, spray granulated in the presence of a coating material, and then dried to form carotenoid microcapsules coated with the coating material.
  • the embodiments of the present application also provide a carotenoid microcapsule prepared by the method for preparing carotenoid microcapsules in any of the above embodiments, wherein the dispersed phase of the carotenoid microcapsule is dispersed in the protective colloid , the average particle size of the dispersed phase is less than 0.7 ⁇ m, the dispersed phase contains at least one carotenoid particle and at least one oil, and the carotenoid particle is encapsulated in the oil in the form of nano-dispersion. Please refer to Figure 4 for details.
  • the average particle size of the carotenoid particles in the carotenoid microcapsules may be 0.05 ⁇ m-0.1 ⁇ m, 0.1 ⁇ m-0.15 ⁇ m or 0.15 ⁇ m-0.2 ⁇ m.
  • the particle size of the dispersed phase of the carotenoid microcapsules may be 0.3 ⁇ m-0.4 ⁇ m, 0.4 ⁇ m-0.5 ⁇ m, 0.5 ⁇ m-0.6 ⁇ m or 0.6 ⁇ m-0.7 ⁇ m.
  • the average particle size of the carotenoid in the mixed dispersion is the average particle size of the carotenoid particles dispersed in the mixed dispersion
  • the average particle size of the dispersed phase of the emulsion is the carotenoid wrapped in the emulsion
  • the average particle size of the oil and fat of the vegetarian particles is the average particle size of the oil in which the carotenoid particles are wrapped when the microcapsules are redispersed in water
  • the average particle size of the carotenoid particles in the microcapsules “Diameter” is the average particle size of the carotenoid particles encapsulated in the oil when the microcapsules are redispersed in water, and the above average particle size is detected by a laser particle size analyzer, a particle imager, or the like.
  • the products prepared in one or more embodiments are mixed with other feed materials, conditioned, puffed, After pelleting and drying, the retention rate of carotenoids in the feed was determined.
  • the carotenoid microcapsules prepared in one or more embodiments were added to the commercial feed, processed into feed by puffing, and cultured rainbow trout for 8 weeks to compare the muscle coloring effect.
  • the outlet is discharged, and the heat exchanger is cooled to the storage tank, which can be recycled.
  • the mixed dispersion liquid of astaxanthin, tocopherol, solvent and soybean oil is obtained in the container, which is circulated into the dispersing device from the injection port through the conveying device, and is in contact with the astaxanthin solution entering the atomization port, and the cycle is repeated until the astaxanthin solution is reached.
  • 8.8Kg of mixed dispersion of astaxanthin, tocopherol, solvent and soybean oil was finally obtained, wherein the content of astaxanthin was 28.4%, the residual solvent was 0.16%, and the average particle size of astaxanthin in the mixed dispersion was 0.171 ⁇ m.
  • the emulsion was desolvated in vacuum for 1 hour, then granulated in a spray granulator, and dried in a fluidized bed to obtain microcapsules containing 10.9% of astaxanthin.
  • the average particle size of the astaxanthin particles was 0.176 ⁇ m, and no methylene chloride residue was detected in the product.
  • the container is kept in a negative pressure state, the vaporized acetone is discharged through the vacuum port, and the heat exchanger is cooled to the storage tank, which can be recycled.
  • the mixed dispersion circulating liquid of astaxanthin, ascorbyl palmitate, solvent and beeswax is obtained in the container, circulated from the injection port into the dispersing device through the conveying device, contacts with the astaxanthin solution entering the atomization port, and circulates back and forth until astaxanthin The delivery of the astaxanthin solution is completed, and finally 11Kg of mixed dispersion liquid of astaxanthin, ascorbyl palmitate, solvent and beeswax is obtained, in which the content of astaxanthin is 22.7%, the residual solvent is 0.13%, and the average particle size of astaxanthin in the mixed dispersion liquid is 0.166 ⁇ m.
  • the average particle size is 0.478 ⁇ m.
  • the emulsion was desolvated in vacuum for 1 hour, then granulated in a spray granulator, and dried in a fluidized bed to obtain microcapsules containing 9.0% of astaxanthin.
  • the average particle size of the dispersed phase of the microcapsules was 0.481 ⁇ m.
  • the average particle size of the astaxanthin particles was 0.168 ⁇ m, and no acetone residue was detected in the product.
  • the mixed dispersion circulating liquid of astaxanthin, BHT, solvent and corn oil is obtained in the container, and circulated through the conveying device from the jet port into the dispersing device, contacted with the astaxanthin solution entering the atomization port, and the cycle reciprocates until the astaxanthin solution After delivery, 13.5Kg of mixed dispersion of astaxanthin, BHT, solvent and corn oil was finally obtained, wherein the content of astaxanthin was 18.5%, the residual solvent was 0.15%, and the average particle size of astaxanthin in the mixed dispersion was 0.161 ⁇ m.
  • the emulsion was desolvated in vacuum for 1 hour, then granulated in a spray granulator, and dried in a fluidized bed to obtain microcapsules containing 7.2% astaxanthin.
  • the average particle size of the astaxanthin particles was 0.162 ⁇ m, and no dichloromethane residue was detected in the product.
  • astaxanthin crystals, tocopherol, and dichloromethane in a mass ratio of 1:0.2:400, and heat up to 40°C to prepare a 0.25% astaxanthin solution.
  • the astaxanthin solution is sprayed at a flow rate of 35Kg/h.
  • the chemical port enters the dispersing device. Rapeseed oil is heated to 100°C through the heating device at a flow rate of 0.35Kg/h together with the circulating dispersion liquid, and enters the dispersion device through the spray port to contact and mix with the atomized astaxanthin solution.
  • the container connected to the dispersing device is kept in a negative pressure state, the vaporized dichloromethane is continuously discharged through the vacuum port, and the heat exchanger is cooled to the storage tank, which can be recycled.
  • the mixed dispersion circulating liquid of astaxanthin, tocopherol, solvent and rapeseed oil is obtained in the container, which is circulated from the injection port into the dispersing device through the conveying device, and is contacted and mixed with the astaxanthin solution entering the atomization port.
  • Dissolving sodium lignosulfonate in water preparing an aqueous solution with a sodium lignosulfonate content of 35%, and keeping the temperature at 40° C. for use.
  • the mixed dispersion with 20% astaxanthin content was sent to the supergravity rotating packed bed beater at a flow rate of 0.455Kg/h, and the prepared sodium lignosulfonate aqueous solution was sent to a flow rate of 2.82Kg/h at the same time.
  • an emulsion with a flow rate of about 3.28 Kg/h was obtained, and the average particle size of the dispersed phase in the emulsion was 0.236 ⁇ m.
  • the above-mentioned emulsion is continuously fed into a spray granulator for granulation, and dried in a fluidized bed to obtain microcapsules containing 5.6% of astaxanthin.
  • the average particle size of the dispersed phase of the microcapsules is 0.241 ⁇ m.
  • the average particle size of the plain particles is 0.109 ⁇ m, and no dichloromethane residue can be detected in the product.
  • astaxanthin crystals, tea polyphenols, and chloroform in a mass ratio of 1:0.7:500, and heat up to 40°C to prepare a 0.2% astaxanthin solution.
  • the astaxanthin solution is atomized at a flow rate of 30Kg/h.
  • the mouth enters the dispersion device.
  • the carnauba wax is heated to 100°C through the heating device with the circulating material at a flow rate of 0.26Kg/h, and then enters the dispersing device through the injection port to contact and mix with the atomized astaxanthin solution.
  • the chloroform vaporizes rapidly, and the material enters and is connected to the dispersing device.
  • the container is kept in a negative pressure state, the vaporized chloroform is continuously discharged through the vacuum port, and the heat exchanger is cooled to the storage tank, which can be recycled.
  • the mixed dispersion circulating liquid of astaxanthin, tocopherol, solvent and carnauba wax is obtained in the container, which is circulated from the injection port into the dispersing device through the conveying device, and is contacted and mixed with the astaxanthin solution entering the atomization port.
  • the starch octenyl succinate was dissolved in water to prepare an aqueous solution with a starch octenyl succinate content of 24%, and the temperature was kept at 40° C. for later use.
  • the mixed dispersion with 18.7% astaxanthin content was sent to the supergravity rotary packed bed beater at a flow rate of 0.36Kg/h, and the prepared sodium lignosulfonate aqueous solution was sent to a flow rate of 1.5Kg/h at the same time.
  • an emulsion with a flow rate of about 1.86 Kg/h was obtained, and the average particle size of the dispersed phase in the emulsion was 0.214 ⁇ m.
  • the above-mentioned emulsion is continuously fed into a spray granulator for granulation, and dried in a fluidized bed to obtain microcapsules containing 6.8% of astaxanthin.
  • the average particle size of the dispersed phase of the microcapsules is 0.225 ⁇ m.
  • the average particle size of the plain particles is 0.120 ⁇ m, and no dichloromethane residue can be detected in the product.
  • Example 1 The processing stability of the astaxanthin microparticles prepared in Example 1, Example 2, Example 3, Example 4, Example 5, Comparative Example 1, and Comparative Example 2 were compared.
  • the astaxanthin particles were mixed with other feed raw materials, conditioned, extruded, granulated, and dried, and the retention rate of astaxanthin in the feed after drying was determined. The results are shown in Table 1 below.
  • Example 1 The astaxanthin microparticles prepared in Example 1, Example 2, Example 4, and Comparative Example 1 were added to commercial feed, and processed into feed A, feed B, feed C, feed D, feed A, B.
  • the measured contents of astaxanthin, C and D were 50ppm, 49ppm, 51ppm and 50ppm, respectively.
  • the rainbow trout were cultured with feeds A, B, C, and D for 8 weeks, respectively, and the muscle coloring effects were compared. The results are shown in Table 2 below.
  • Table 2 Effects of different astaxanthin diets on muscle pigmentation in rainbow trout at 8 weeks
  • the device is connected to the container, the container is kept in a negative pressure state, the vaporized chloroform is discharged through the vacuum port, and the heat exchanger is cooled to the storage tank, which can be recycled.
  • the mixed dispersion circulating liquid of cantharidin, ethoxyquin, solvent and hydrogenated palm oil is obtained in the container, and is circulated into the dispersing device from the injection port through the conveying device, and is in contact with the cantharidin solution entering the atomization port, and the cycle is repeated until the cantharidin After delivery of the yellow solution, 14Kg of mixed dispersion of cantharidin, ethoxyquin, solvent and hydrogenated palm oil is finally obtained, wherein the content of cantharidin is 8.9%, the solvent residue is 0.23%, and the average particle size of cantharidin in the mixed dispersion is 0.131 ⁇ m.
  • Dissolve 37.5Kg of sodium lignosulfonate in 62.5Kg of water keep the temperature at 65°C, mix the above mixed dispersion with an aqueous solution of sodium lignosulfonate, and emulsify at high speed for 30min to obtain an emulsion with an average particle size of the dispersed phase of the emulsion. 0.355 ⁇ m.
  • the emulsion was desolvated in vacuum for 1 hour, then granulated in a spray granulator, and dried in a fluidized bed to obtain microcapsules containing 2.0% of cantharidin.
  • the average particle size of the dispersed phase of the microcapsules was 0.362 ⁇ m.
  • the average particle size of the cantharidin granules was 0.133 ⁇ m, and no chloroform residue was detected in the product.
  • lycopene crystals, tocopherol, and dichloromethane in a mass ratio of 1:0.2:800, raise the temperature to 40°C, and prepare a 0.12% lycopene solution.
  • the lycopene solution is sprayed at a flow rate of 20Kg/h.
  • the chemical port enters the dispersing device. Rapeseed oil is heated to 100°C through the heating device at a flow rate of 0.49Kg/h together with the circulating material, and enters the dispersing device through the injection port to contact and mix with the atomized lycopene solution, the dichloromethane is rapidly vaporized, and the material enters and disperses.
  • the container connected to the device is kept in a negative pressure state, the vaporized dichloromethane is continuously discharged through the vacuum port, and the heat exchanger is cooled to the storage tank, which can be recycled.
  • the mixed dispersion circulating liquid of lycopene, tocopherol, solvent and rapeseed oil is obtained in the container, which is circulated from the injection port into the dispersing device through the conveying device, and is contacted and mixed with the lycopene solution entering the atomization port.
  • Dissolving sodium lignosulfonate in water preparing an aqueous solution with a sodium lignosulfonate content of 35%, and keeping the temperature at 40° C. for use.
  • the mixed dispersion with 4.8% lycopene content was sent to the supergravity rotating packed bed beater at a flow rate of 0.52Kg/h, and the prepared sodium lignosulfonate aqueous solution was sent to a flow rate of 3.3Kg/h at the same time.
  • an emulsion with a flow rate of about 3.8 Kg/h was obtained, and the average particle size of the dispersed phase in the emulsion was 0.286 ⁇ m.
  • the above-mentioned emulsion is continuously fed into a spray granulator for granulation, and dried in a fluidized bed to obtain microcapsules containing 1.2% lycopene.
  • the average particle size of the dispersed phase of the microcapsules is 0.292 ⁇ m.
  • the average particle size of the plain particles is 0.111 ⁇ m, and no dichloromethane residue can be detected in the product.
  • ⁇ -Carotene crystals, ascorbyl palmitate, and dichloromethane were mixed in a mass ratio of 1:0.4:1600, and the temperature was raised to 40°C to prepare a 0.06% ⁇ -carotene solution.
  • the ⁇ -carotene solution was 25Kg/h
  • the flow rate enters the dispersing device through the atomization port.
  • the palm oil is heated to 100 °C through the heating device at a flow rate of 0.59Kg/h together with the circulating material, and then enters the dispersing device through the spray port to contact and mix with the atomized beta-carotene solution, the dichloromethane is rapidly vaporized, and the material enters and disperses.
  • the container connected to the device is kept in a negative pressure state, the vaporized dichloromethane is continuously discharged through the vacuum port, and the heat exchanger is cooled to the storage tank, which can be recycled.
  • the mixed dispersion circulating liquid of ⁇ -carotene, tocopherol, solvent and palm oil is obtained in the container, circulated through the conveying device from the injection port into the dispersing device, contacted and mixed with the ⁇ -carotene solution entering the atomization port, and obtained after the system is stabilized.
  • the gelatin was dissolved in water, an aqueous solution with a gelatin content of 21.4% was prepared, and the temperature was kept at 40° C. for use.
  • the mixed dispersion with 2.4% ⁇ -carotene content was sent to the supergravity rotary packed bed beater at a flow rate of 0.65Kg/h, and the prepared sodium lignosulfonate aqueous solution was sent at a flow rate of 3.65Kg/h. into the above-mentioned supergravity rotating bed beater to obtain an emulsion with a flow rate of about 4.3 Kg/hour, and the average particle size of the dispersed phase of the emulsion is 0.332 ⁇ m.
  • the above-mentioned emulsion is continuously fed into a spray granulator for granulation, and dried in a fluidized bed to obtain microcapsules containing 1.0% of beta-carotene.
  • the average particle size of the dispersed phase of the microcapsules is 0.343 ⁇ m.
  • the average particle size of the carotene particles is 0.089 ⁇ m, and no methylene chloride residue can be detected in the product.

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Abstract

一种稳定的、高生物利用度的类胡萝卜素微胶囊及其制备方法，方法包括如下步骤：a)将类胡萝卜素结晶与有机溶剂混合、溶解，得到类胡萝卜素溶液；b)将类胡萝卜素溶液与热油脂通入分散系统，使类胡萝卜素充分分散至热油脂，并使有机溶剂汽化，得到类胡萝卜素混合分散液；c)将类胡萝卜素混合分散液与保护性胶体水溶液混合乳化得到乳状液；d)喷雾造粒并干燥得到类胡萝卜素微胶囊。

Description

一种稳定、高生物利用度的类胡萝卜素微胶囊及其制备方法
相关申请
本申请要求2020年7月31日申请的，申请号为202010756509.4，发明名称为“一种稳定、高生物利用度的类胡萝卜素微胶囊及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本申请涉及医药化工领域，特别是涉及一种稳定、高生物利用度的类胡萝卜素微胶囊及其制备方法。
背景技术
类胡萝卜素是一类带有多个不饱和键的多烯化合物，作为最重要的天然色素之一，其具有广泛生物活性，包括维生素A原、抗氧化功能、抗肿瘤、保护眼睛以及预防心血管疾病、防止骨质疏松、促进减肥以及保护皮肤等多种功效，已越来越引起医药、食品、饲料、水产养殖以及化妆品等领域相关研究人员的重视。
由于大部分的类胡萝卜素都不溶于水，在植物油的溶解度也很小，在食品加工过程及储藏过程中很容易受化学物质、机械、光、氧、热等作用而高度不稳定，从而限制了它们在功能性食品中的应用。此外，作为微量营养素，类胡萝卜素的生理功效主要取决于其在机体的生物利用率，大量研究表明，类胡萝卜素的存在形式及其粒径对其生物利用率影响很大，类胡萝卜素颗粒粒径越小意味着其被生物体摄入后越容易被吸收利用，也就是拥有更高的生物利用度，所以人们总是努力降低类胡萝卜素颗粒径，让其达到微米级甚至纳米级，因此目前类胡萝卜素开发研究的热点在于：选择颗粒细、稳定性好、生物利用率高的制剂剂型作为类胡萝卜素的摄入载体。
目前市场上出现了各种各样的添加单一或多种类胡萝卜素的健康食品、以及膳食补充剂，如各种片剂、硬胶囊、软胶囊和一些适于装填软胶囊的类胡萝卜素的油悬液、微胶囊、纳米乳、脂质体。但软胶囊、纳米乳、脂质体这三类制剂在制备过程中所添加的表面活性剂可能引发副作用，并引起人体的过敏反应，且软胶囊、乳剂、脂质体都存在易分层及易氧化变质等问题，从而限制了其应用。
在文献中，已有多种剂型的类胡萝卜素制剂的制备方法被报道：
CN101828693A通过利用四氢呋喃、乙醇、植物油等处理类胡萝卜素粗结晶而得到粒径约为10μm的类胡萝卜素油悬液；CN102552173B利用将类胡萝卜素溶液以雾化方式进入植物油的工艺得到平均粒径小于5μm的类胡萝卜素油悬浮液；但这2个工艺的均匀性 和类胡萝卜素的粒径均无法达到乳液的水平。且类胡萝卜素在油溶液中化学稳定性很差，极易发生副反应，再者，油悬液剂型在饲料、食品及保健品行业应用不够方便。
CN108030063A以β-胡萝卜素、单甘酯、甘油三酯及维生素E作为油相，经过140-250℃油浴加热的盘管换热器，至油悬液中β-胡萝卜素完全熔融后，加入壁材溶液乳化，辅以消化促进剂，经过喷雾干燥，得到β-胡萝卜素微胶囊。但是高温熔融法容易导致营养素在高温下发生降解或异构化，降低其生物活性。
US3998753记载了一种水可分散的类胡萝卜素制备方法，其中类胡萝卜素的粒度小于1μm，该方法是先将类胡萝卜素与其他添加剂配成有机溶剂的溶液，然后加入到含明胶、分散剂、稳定剂的水溶液中，经高速剪切使体系形成乳液；除去有机溶剂，喷雾干燥得到所需粉末；US4522743所记载的制备水分散的类胡萝卜素粉的方法，是将类胡萝卜素于50～200℃于10秒内溶解在挥发性水可混溶的溶剂中，然后于0℃～50℃下与含保护性胶体的水溶液快速混合，类胡萝卜素即以＜0.5μm的尺寸分散于保护性胶体中，脱除溶剂，干燥可得类胡萝卜素粉。上述工艺需要在高压(压力在3.0MPa～6.0MPa)、高温(170℃～200℃)进行，对设备要求高，操作、控制难度大。且这2个工艺均需在保护性胶体中脱除体系中所含的大量溶剂，所需时间长，不易脱除干净，在保护性胶体存在下加热脱溶，体系极易起泡，脱溶时的效率很低，不易控制所需类胡萝卜素粉的粒径和色泽。
CN107669657A采用将类胡萝卜素溶于有机溶剂中形成油相，与乳化稳定剂与水溶解后形成的水相乳化后，在乳液中升温去除溶剂，再加入包被性壁材均质，通过造粒干燥制备较为稳定的类胡萝卜素干粉或微粒。US6936279B2中揭示了一种方法制备类胡萝卜素油悬浮液，其中先将类胡萝卜素与某种非水溶性溶剂混合，再与植物油混合后在氮气流作用下雾化，收集雾化后的溶液，回收其中溶剂，便得到类胡萝卜素油悬液。上述2种方法中，为了保证类胡萝卜素的稳定性，需要额外加入乳化稳定剂或者加入大量的乳化剂和水，而且为了去除大量的有机溶剂，在收集一定量雾化后的“浓缩液”后要停下雾化操作而进行溶剂回收，这在工业化生产上是不利的，此方法产量不大，只适于实验室规模。
为了解决现有技术的问题，我们于2005年申请了一种水分散性类胡萝卜素粉的制备方法(CN100421650C)，该法是将类胡萝卜素结晶溶于含有抗氧化剂、乳化剂的卤代烃或酯类溶剂中，所得的溶液以喷雾形式加入到高速搅拌的乙醇或异丙醇中，使类胡萝卜素以<2μm的无定形粉末形态析出；然后用滤膜或烧结滤棒过滤析出的类胡萝卜素，滤饼以乙醇或异丙醇洗涤，滤干；再将滤饼加入含有保护性胶体的水溶液中，先搅拌打浆，后经均质乳化，接着脱除残余溶剂，制成水分散液；最后将所述的分散液用喷雾法造粒，再经流态化干燥得到水分散性类胡萝卜素的制剂。该方法中通过双溶剂法进行工艺创新，大幅缩短 脱溶时间，但类胡萝卜素粒径还需进一步细化，且生物利用度还有待进一步提高。
根据分子营养学可知，要实现类胡萝卜素的生物利用，就要最大限度地避免其在消化道中被破坏和降解，使之能顺利到达肠道部位，与游离脂肪酸、单甘酯和胆盐共同形成为微胶束，从而被小肠粘膜细胞吸收，由淋巴循环系统带入到体内各器官发挥其保健功效。
针对现有技术的缺陷，以及类胡萝卜素在机体内消化吸收的特点，本申请希望找到一种高效简单的方法，能够快速脱除有机溶剂，得到的类胡萝卜素制剂中颗粒细、包埋效果好、稳定性及生物利用度高的产品。
发明内容
本申请的所要解决的技术问题是针对现有技术的现状，提供一种颗粒细、生物利用度高、稳定性好的类胡萝卜素微胶囊及其制备方法。
一种稳定、高生物利用度的类胡萝卜素微胶囊的制备方法，所述方法包括如下步骤：
a)将类胡萝卜素结晶与有机溶剂混合，溶解，得到类胡萝卜素溶液；
b)将所述类胡萝卜素溶液与热油脂通入分散系统，使类胡萝卜素充分分散至所述热油脂中，并使有机溶剂汽化，得到类胡萝卜素混合分散液；
c)将所得类胡萝卜素混合分散液与保护性胶体的水溶液混合，进行乳化得到乳状液；
d)将所述乳状液进行喷雾造粒，然后干燥，得到类胡萝卜素微胶囊。
在其中一个实施例中，步骤b)所述分散系统包括分散装置、连接所述分散装置的容器、输送装置和加热装置，所述分散装置用于步骤a)得到的类胡萝卜素溶液与热油脂或循环物料接触，使类胡萝卜素充分分散到所述热油脂中；所述输送装置用于将物料在所述分散系统中传输；所述加热装置用于将油脂或所述循环物料加热为液态。
在其中一个实施例中，所述分散装置包括依次连接的接触段、收缩段及扩张段；
所述接触段设置有喷射口和雾化口，所述喷射口将加热的液态热油脂或循环物料经所述喷射口引入所述接触段；所述雾化口将步骤a)得到的类胡萝卜素溶液经所述雾化口形成微小的雾滴，引入所述接触段，与呈喷射状的液态热油脂或循环物料接触混合，使所述类胡萝卜素溶液中的有机溶剂汽化，形成类胡萝卜素颗粒并分散在所述热油脂中；
所述收缩段进一步将所述接触段形成的类胡萝卜素雾滴与油脂混合，蒸发所述有机溶剂，进入所述扩张段，再进入与所述分散装置连接的所述容器中。
在其中一个实施例中，所述连接分散装置的容器还包括真空口，将汽化的所述有机溶剂通过所述真空口排出所述容器。
在其中一个实施例中，所述分散系统为连续操作或间歇操作。
在其中一个实施例中，所述物料在所述分散系统中的停留时间≤20h，可选≤10h。
在其中一个实施例中，所述热油脂的温度为60℃-100℃。
在其中一个实施例中，步骤b)中仅将所述类胡萝卜素溶液中的部分所述有机溶剂汽化脱除，可选的，所述类胡萝卜素混合分散液中的残留所述有机溶剂的含量低于1％，可选低于0.5％，可选低于0.2％。
在其中一个实施例中，步骤c)还包括：进行乳化后脱除所述乳状液中的残留有机溶剂的步骤。
在其中一个实施例中，类胡萝卜素以部分溶解及颗粒分散的状态存在于步骤b)得到的所述类胡萝卜素混合分散液中。在其中一个实施例中，所述类胡萝卜混合分散液中的类胡萝卜素颗粒的平均粒径为0.05μm-0.2μm。
在其中一个实施例中，所述步骤b)中，所述热油脂与类胡萝卜素结晶的质量比为0.7:1-20:1，可选为1:1-10:1。
在其中一个实施例中，步骤c)所述的乳化方法为高压均质乳化、在线管道式高剪切乳化、超重力乳化和静态混合中的一种或多种。
在其中一个实施例中，所述保护性胶体选自明胶、辛烯基琥珀酸淀粉酯、阿拉伯胶、木质素磺酸钠、木质素磺酸钙、聚丙烯酸钠和羧甲基纤维素钠中的一种或多种。
在其中一个实施例中，经过步骤c)所述的乳化，所述混合分散液分散在所述保护性胶体中，分散相平均粒径＜0.7μm，所述分散相包含至少一种类胡萝卜素颗粒、至少一种油脂，所述类胡萝卜素颗粒以纳米分散的形式被包裹在所述油脂中。
在其中一个实施例中，步骤a)的所述有机溶剂选自氯仿、二氯甲烷、乙酸乙酯、乙酸丙酯、丙酮和丙醇中的一种或多种。
在其中一个实施例中，步骤a)中所述有机溶剂与所述类胡萝卜素结晶的质量比为100:1-2000:1。
在其中一个实施例中，所述类胡萝卜素溶液中添加有抗氧化剂，所述抗氧化剂选自TBHQ、VC-棕榈酸酯、生育酚、迷迭香、茶多酚、没食子酸丙酯、BHT、抗坏血酸钠、抗坏血酸和乙氧基喹啉中的一种或多种；和/或，所述抗氧化剂与所述类胡萝卜素结晶的质量比为0.1:1-3:1。
在其中一个实施例中，所述步骤b)中的所述热油脂为生理上可接受的油脂，所述油脂选自蜡类、植物油脂和氢化植物油脂中的一种或多种。
在其中一个实施例中，所述蜡类选自蜂蜡、巴西棕榈蜡、小烛树蜡、微晶蜡、褐煤酸酯蜡、稻芽油蜡、鲸蜡、羊毛脂蜡、西门德木蜡、萨索尔蜡和日本蜡中的一种或多种，可选蜂蜡；和/或，所述植物油脂选自玉米油、大豆油、葵花籽油、橄榄油、椰子油、菜籽油、 棉籽油、棕榈油、棕榈硬脂和可可脂中的一种或多种；和/或，所述氢化植物油脂选自氢化棉籽油、氢化棕榈油和氢化大豆油中的一种或多种。
在其中一个实施例中，步骤a)的所述类胡萝卜素结晶选自β-胡萝卜素、叶黄素、玉米黄质、番茄红素、角黄素、虾青素、辣椒红素、柠檬黄素、β-阿朴-8’-胡萝卜素醛、β-阿朴-8’-胡萝卜素酸乙酯中的一种或多种。
一种所述类胡萝卜素微胶囊制备方法得到的稳定、高生物利用度的类胡萝卜素微胶囊，所述类胡萝卜素微胶囊的分散相分散在所述保护性胶体中，分散相平均粒径＜0.7μm，所述分散相包含至少一种类胡萝卜素颗粒、至少一种油脂，所述类胡萝卜素颗粒以纳米分散的形式被包裹在所述油脂中。
在本申请的工艺中，将类胡萝卜素结晶预先溶解于含有抗氧剂的有机溶剂中得到类胡萝卜素溶液，采用分散系统，使类胡萝卜素溶液经雾化口形成微小的雾滴，与喷射状态的热油脂或循环物料接触，从喷射口引入的热油脂或循环物料产生负压，且温度高于有机溶剂的沸点，在与类胡萝卜素溶液形成的雾滴接触过程中使机溶剂迅速汽化，形成类胡萝卜素颗粒并分散在油脂中，溶液中的类胡萝卜素以分子状态析出并生长，由于混合分散液体系中的残留溶剂和热油脂对类胡萝卜素仍有一定的溶解度，导致类胡萝卜素的析出受到明显抑制，在高速混合条件下，颗粒粒径能被控制在纳米级；进一步的，分散装置接触段形成的物料进入收缩段时，类胡萝卜素溶液雾滴与油脂进一步混合，使雾滴中的有机溶剂蒸发，得到类胡萝卜素混合分散液，在此过程中避免类胡萝卜素油脂分散液聚集，变大，且汽化的有机溶剂在与分散装置连接的容器中经真空口排出系统。相较于传统制备方法(类胡萝卜素溶液在水溶性胶体作用下边乳化边常压脱溶)，本申请形成的类胡萝卜分散液中的类胡萝卜素可达到细小的颗粒级别。
将得到的混合分散液与保护性胶体的水溶液混合乳化，并脱除剩余的溶剂，再造粒成型。微胶囊中的类胡萝卜素颗粒以纳米分散的形式被包裹在油脂中，油脂的存在能为其中的类胡萝卜素颗粒提供致密保护,隔绝氧气，使产品具有更好的加工稳定性。
本申请微胶囊被摄入动物体内后，在强酸性的胃液环境中，油脂的存在隔绝了胃酸对类胡萝卜素的破坏作用，使产品具有更好的化学稳定性，之后类胡萝卜素颗粒、油脂在小肠中分解后与其他脂类物质一起经胆汁乳化后形成微团,自由扩散进入肠黏膜细胞。类胡萝卜素颗粒粒径小，且被油脂包裹更易与饲料中的脂类物质一起经胆汁乳化，更有效的形成微团被动物吸收，产品生物利用度高。
本申请至少包括以下的有益效果：
1)采用热油脂进行分散，混合分散液体系中的残留溶剂和热油脂对类胡萝卜素仍有 一定的溶解度，导致类胡萝卜素的析出受到明显抑制，在高速混合条件下，颗粒粒径能被控制在纳米级。
2)本申请有机溶剂在分散体系中在线脱除，可大大简化操作步骤。
3)本申请微胶囊中的类胡萝卜素颗粒以纳米分散的形式被包裹在油脂中，油脂的存在能为其中的类胡萝卜素颗粒提供致密保护，隔绝氧气，使产品具有更好的加工稳定性。
4)本申请微胶囊被摄入动物体内后，在强酸性的胃液环境中，油脂的存在隔绝了胃酸对类胡萝卜素的破坏作用，使产品具有更好的化学稳定性。
5)本申请微胶囊中的类胡萝卜素颗粒粒径小，且被油脂包裹更易与饲料中的脂类物质一起经胆汁乳化，更有效的形成微团被动物吸收，产品的生物利用度高。
附图说明
图1为本申请一实施例的类胡萝卜素微胶囊制备方法流程示意图。
图2为本申请一实施例的分散系统结构示意图，其中，1—分散装置；2—容器；3—输送装置；4—加热装置。
图3为本申请一实施例的分散装置示意图，其中，5—喷射口；6—雾化口；7—接触段；8—收缩段；9—扩张段。
图4为本申请一实施例的类胡萝卜素微胶囊结构示意图。
具体实施方式
为了便于理解本申请，下面将参照相关附图对本申请进行更全面的描述。附图中给出了本申请的一些实施例。但是，本申请可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使对本申请的公开内容的理解更加透彻全面。基于本申请中的实施方式，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施方式，都属于本申请保护的范围。
除非另有定义，本文所使用的所有的技术和科学术语与属于本申请的技术领域的技术人员通常理解的含义相同。本文中在本申请的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本申请。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
请参阅图1，本申请提供一种类胡萝卜素微胶囊的制备方法，包括如下步骤：
a)将类胡萝卜素结晶与有机溶剂混合，溶解，得到类胡萝卜素溶液；
b)将所述类胡萝卜素溶液与热油脂通入分散系统，使类胡萝卜素充分分散至所述热油脂中，并使有机溶剂迅速汽化，得到类胡萝卜素混合分散液；
c)所得类胡萝卜素混合分散液与保护性胶体的水溶液混合，进行乳化得到乳状液；
d)将所述乳状液进行喷雾造粒，然后干燥，得到类胡萝卜素微胶囊。
在本申请中，若无特别说明，则所用原料(例如有机溶剂、油脂等)均为生理上可接受的物质。
术语“至少大部分”指大于50％、可选≥60％、≥70％、≥80％、≥90％、≥95％、≥96％、≥97％、≥98％或≥99％。
本申请采用热油脂对类胡萝卜素进行分散，混合分散液体系中的热油脂和部分有机溶剂对类胡萝卜素仍有一定的溶解度，导致类胡萝卜素的析出受到明显抑制，在高速混合条件下，类胡萝卜素的颗粒粒径能被控制在纳米级。并且，油脂的存在，还能为其中的类胡萝卜素颗粒提供致密的保护，隔绝氧气、胃酸，使得产品具有更好的加工稳定性及化学稳定性。相对现有技术的常规溶剂法或者研磨法，本申请得到的类胡萝卜素微胶囊中类胡萝卜素颗粒的粒径控制得更小，且类胡萝卜素颗粒被油脂包裹更易与饲料中的脂类物质一起经胆汁乳化，更有效的形成微团被动物吸收，产品生物利用度高。
在一实施例中，步骤a)的所述类胡萝卜素结晶选自β-胡萝卜素、叶黄素、玉米黄质、番茄红素、角黄素、虾青素、辣椒红素、柠檬黄素、β阿朴-8’-胡萝卜素醛、β-阿朴-8’-胡萝卜素酸乙酯中的一种或多种。
在一实施例中，步骤a)的所述有机溶剂可选自氯仿、二氯甲烷、乙酸乙酯、乙酸丙酯、丙酮和丙醇中的一种或多种。
在一实施例中，步骤a)中所述有机溶剂与所述类胡萝卜素结晶的质量比为100:1-2000:1。具体的，有机溶剂与类胡萝卜素结晶的质量比可以为100:1-500:1、500:1-800:1、800:1-1000:1、1000:1-1200:1、1200:1-1400:1、1400:1-1700:1或1700:1-2000:1。
在一实施例中，所述类胡萝卜素溶液中添加有抗氧化剂，所述抗氧化剂选自TBHQ、VC-棕榈酸酯、生育酚、迷迭香、茶多酚、没食子酸丙酯、BHT、抗坏血酸钠、抗坏血酸和乙氧基喹啉中的一种或多种。在一实施例中，所述抗氧化剂与所述类胡萝卜素结晶的质量比为0.1:1-3:1。
在一实施例中，可通过加热方式使得胡萝卜素结晶完全溶解于有机溶剂中。
在一实施例中，所述步骤b)中的所述热油脂为生理上可接受的油脂，所述油脂选自蜡类、植物油脂和氢化植物油脂中的一种或多种。在一实施例中，所述蜡类选自蜂蜡、巴西棕榈蜡、小烛树蜡、微晶蜡、褐煤酸酯蜡、稻芽油蜡、鲸蜡、羊毛脂蜡、西门德木蜡、萨索尔蜡和日本蜡中的一种或多种，可选为蜂蜡。在一实施例中，所述植物油脂选自玉米油、大豆油、葵花籽油、橄榄油、椰子油、菜籽油、棉籽油、棕榈油、棕榈硬脂和可可脂中的一种或多种。在一实施例中，所述氢化植物油脂选自氢化棉籽油、氢化棕榈油和氢化大豆 油中的一种或多种。
在一实施例中，所述热油脂的温度为60℃-100℃。具体可以为60℃-70℃、70℃-80℃、80℃-90℃或90℃-100℃。
请参阅图2和图3，在一个实施例中，所述步骤b)所述分散系统包括分散装置1、连接分散装置1的容器2、输送装置3和加热装置4，所述分散装置1用于步骤a)得到的类胡萝卜素溶液与热油脂或循环物料接触，使类胡萝卜素充分分散到油脂中；所述输送装置3用于系统物料输送；所述加热装置4用于加热油脂或循环物料使其呈液态。可选的，所述分散系统为循环传输系统，即分散装置中的物料能够进入容器，容器中的物料又能够循环回流入所述分散装置。所述循环物料指的是类胡萝卜素溶液经所述分散装置一次或多次除有机溶剂之后再次在所述分散系统中传输的组分。
在一个实施例中，所述分散装置1包括依次连接的接触段7、收缩段8及扩张段9，所述接触段7设置有喷射口5和雾化口6，所述喷射口5将加热的液态热油脂或循环物料经喷射口5引入接触段7；所述雾化口6将步骤a)得到的类胡萝卜素溶液经雾化口6形成微小的雾滴，引入接触段7，与呈喷射状的液态热油脂或循环物料接触混合，使类胡萝卜素溶液中的有机溶剂汽化，形成类胡萝卜素颗粒并分散在油脂中。
所述收缩段8进一步将接触段7形成的类胡萝卜素雾滴与油脂混合，快速蒸发有机溶剂，进入扩张段9，再进入与分散装置1连接的容器2中。
在一个实施例中，所述与分散装置1的容器2还包括真空口，将汽化的有机溶剂通过真空口排出容器2。
在一个实施例中，所述分散系统为连续操作或间歇操作。连续操作指的是类胡萝卜素溶液连续的进入所述分散系统进行处理，例如类胡萝卜素溶液以预定的速度连续进入所述分散系统，如实施例7所示。间歇操作指的是将类胡萝卜素一次性进料至所述分散系统，分散系统中反应完成的物料再进行后续的步骤得到乳状液并造粒，得到类胡萝卜素微胶囊，如实施例1所示。
在一个实施例中，所述物料在分散系统中的停留时间≤20h，可选≤10h。
请参阅图3，在一实施例中，步骤b)中，所述热油脂或循环物料经喷射口5进入分散装置1的接触段7，与所述类胡萝卜素溶液经分散装置1的雾化口6形成的雾滴接触，热油脂或循环物料的温度高于有机溶剂的沸点，在与雾化的雾滴接触时使类胡萝卜素溶液中的有机溶剂迅速汽化，形成类胡萝卜素颗粒并分散在油脂中，物料经收缩段8、扩张段9进入容器2后，汽化的有机溶剂经容器2上方的真空口排出，得到类胡萝卜素混合分散液，经输送装置3循环往复，待混合分散液中类胡萝卜素的颗粒达到0.05μm-0.2μm时， 出料进行步骤c)。
可选的，步骤b)将所述类胡萝卜素溶液中的至少大部分有机溶剂脱除。可选的，步骤b)中仅将所述类胡萝卜素溶液中的部分所述有机溶剂汽化脱除，残留有机溶剂可在乳化后脱除。混合分散液中部分有机溶剂和热油脂对类胡萝卜素仍有一定的溶解度，导致类胡萝卜素的析出受到明显抑制，在高速混合条件下，颗粒粒径能被控制在纳米级。在一实施例中，在步骤b)中脱出有机溶剂的质量百分比＞99％。在一实施例中，所述类胡萝卜素溶液经喷雾后与所述热油脂接触，在负压体系下脱除部分有机溶剂。具体的脱除时间根据实际的溶剂量、脱除比例要求和实际体系情况确定。
在一实施例中，控制所述类胡萝卜素混合分散液中的残留的所述有机溶剂的质量含量低于1％(小于等于1％)，可选低于0.5％(小于等于0.5％)，可选低于0.2％(小于等于0.2％)。在一实施例中，步骤c)还包括：进行乳化后脱除乳状液中的残留有机溶剂的步骤。具体的脱溶剂方法可以为常规方法，例如真空脱溶。具体的脱除时间根据实际的存留溶剂量和实际体系情况确定。
在一实施例中，类胡萝卜素以部分溶解及颗粒分散的状态存在于步骤b)得到的所述类胡萝卜素混合分散液中。可选的，类胡萝卜素至少大部分以颗粒分散的状态存在于所述类胡萝卜素混合分散液中，即类胡萝卜素大部分以颗粒状分散，小部分溶解于类胡萝卜素混合分散液中。可选以＞80％的部分以颗粒分散的状态存在于所述类胡萝卜素混合分散液中。
在一实施例中，所述类胡萝卜混合分散液中的类胡萝卜素颗粒的平均粒径为0.05μm-0.2μm。具体的，类胡萝卜素颗粒的粒径可以为0.05μm-0.1μm、0.1μm-0.15μm或0.15μm-0.2μm。
在一实施例中，所述热油脂与类胡萝卜素结晶的质量比为(0.7-20):1。具体的，热油脂与类胡萝卜素结晶的质量比可以为0.7:1-1:1、1:1-5:1、5:1-10:1、10:1-15:1、15:1-20:1。可选为1:1-10:1。
在一实施例中，步骤c)所述的乳化方法为高压均质乳化、在线管道式高剪切乳化、超重力乳化和静态混合中的一种或多种。可选的，乳化方法可为高压均质乳化。
在一实施例中，所述保护性胶体可选自明胶、辛烯基琥珀酸淀粉酯、阿拉伯胶、木质素磺酸钠、木质素磺酸钙、聚丙烯酸钠和羧甲基纤维素钠中的一种或多种。
在本申请优选的工艺中，将类胡萝卜素结晶预先溶解于含有抗氧剂的有机溶剂中得到类胡萝卜素溶液，再经分散体系雾化成雾滴，与呈喷射状态的热油脂接触，在此过程中类胡萝卜素溶液中的有机溶剂快速蒸发，使溶液中的类胡萝卜素以分子状态析出并生长，由 于混合分散液体系中的残留溶剂和热油脂对类胡萝卜素仍有一定的溶解度，导致类胡萝卜素的析出受到明显抑制，在高速混合条件下，颗粒粒径能被控制在纳米级；且相较于传统制备方法(类胡萝卜素溶液在水溶性胶体作用下边乳化边常压脱溶)，本申请有机溶剂在线脱除，可大大简化操作步骤。
将得到的混合分散液再与保护性胶体的水溶液中混合乳化，并脱除剩余的溶剂，再造粒成型。产品中油脂的存在还能为其中的类胡萝卜素颗粒提供致密保护。
在一实施例中，经过步骤c)所述的乳化，所述混合分散液分散在所述保护性胶体中，分散相平均粒径＜0.7μm，所述分散相包含至少一种类胡萝卜素颗粒、至少一种油脂，所述类胡萝卜素颗粒以纳米分散的形式被包裹在所述油脂中。
在一实施例中，步骤d)的喷雾造粒，在涂敷材料存在的条件下进行喷雾造粒。可选的，涂敷材料选自玉米淀粉、二氧化硅、磷酸三钙及其混合物。
在一实施例中，步骤d)的干燥方法可以为流化床干燥。
在一实施例中，所述乳状液进料到喷雾造粒塔中，在涂敷材料存在的条件下进行喷雾造粒，然后干燥，形成包覆涂敷材料的类胡萝卜素微胶囊。本申请实施例还提供了一种由上述任一实施例的类胡萝卜素微胶囊的制备方法制备得到的类胡萝卜素微胶囊，该类胡萝卜素微胶囊的分散相分散在所述保护性胶体中，分散相平均粒径＜0.7μm，所述分散相包含至少一种类胡萝卜素颗粒、至少一种油脂，所述类胡萝卜素颗粒以纳米分散的形式被包裹在所述油脂中。具体可请参阅图4所示。
在一实施例中，该类胡萝卜素微胶囊中的类胡萝卜素颗粒的平均粒径可以为0.05μm-0.1μm、0.1μm-0.15μm或0.15μm-0.2μm。
在一实施例中，该类胡萝卜素微胶囊的分散相的粒径可以为0.3μm-0.4μm、0.4μm-0.5μm、0.5μm-0.6μm或0.6μm-0.7μm。
本申请中“混合分散液中类胡萝卜素的平均粒径”为分散在混合分散液中的类胡萝卜素颗粒的平均粒径，“乳状液分散相平均粒径”为乳状液中包裹着类胡萝卜素颗粒的油脂的平均粒径，“微胶囊分散相平均粒径”为微胶囊再分散于水中时其中包裹着类胡萝卜素颗粒的油脂的平均粒径，“微胶囊中类胡萝卜素颗粒平均粒径”为微胶囊再分散于水中时被包裹在油脂中的类胡萝卜素颗粒的平均粒径，上述平均粒径采用激光粒度仪、颗粒图像仪等检测。
在本申请的一个或几个实施例中，为了检测本申请所制备的类胡萝卜素微胶囊的稳定性，将一个或几个实施例制备得到的产品与其他饲料原料混合、调质、膨化、制粒、烘干，测定烘干后饲料中类胡萝卜素的保留率。
为了评价产品的生物利用度，将一个或几个实施例制备得到的类胡萝卜素微胶囊加入 到商品饲料中，经膨化加工制成饲料，并养殖虹鳟8周，对肌肉着色效果进行对比。
以下为具体的实施例。
实施例1：
将2.5Kg虾青素结晶、0.3Kg生育酚与250Kg二氯甲烷混合，升温至40℃，制成0.99％的虾青素溶液。将1Kg生育酚加入到5Kg大豆油中，用循环泵将该混合物经加热装置升温至80℃，经喷射口进入分散装置。虾青素溶液经雾化口进入分散装置，与呈喷射状态的循环物料接触混合，二氯甲烷迅速汽化，物料进入与分散装置连接的容器，容器保持负压状态，汽化的二氯甲烷经真空口排出，热交换器冷却到贮罐，可以循环使用。容器中得到虾青素、生育酚、溶剂和大豆油的混合分散液，经输送装置从喷射口循环进入分散装置，与雾化口进入的虾青素溶液接触，循环往复，直至虾青素溶液输送完毕，最终得到虾青素、生育酚、溶剂和大豆油的混合分散液8.8Kg，其中虾青素含量28.4％，溶剂残留0.16％，混合分散液中虾青素的平均粒径0.171μm。
将10Kg明胶溶解于40Kg水中并降温至40℃，将上述混合分散液与明胶水溶液混合，高速剪切乳化30min，得到乳状液，乳状液分散相平均粒径0.501μm。乳状液真空脱溶1小时，然后在喷雾造粒器中造粒，经流化床干燥，即得含虾青素10.9％的微胶囊，微胶囊的分散相平均粒径为0.512μm，微胶囊中虾青素颗粒的平均粒径为0.176μm，产品中检测不到二氯甲烷残留。
实施例2：
将2.5Kg虾青素结晶、1Kg抗坏血酸棕榈酸酯与300Kg丙酮混合，升温至55℃，制成0.82％的虾青素溶液。将7.5Kg蜂蜡经加热装置升温至100℃，经喷射口进入分散装置，虾青素溶液经雾化口进入分散装置，与呈喷射状态的蜂蜡接触混合，丙酮迅速汽化，物料进入与分散装置连接的容器，容器保持负压状态，汽化的丙酮经真空口排出，热交换器冷却到贮罐，可以循环使用。容器中得到虾青素、抗坏血酸棕榈酸酯、溶剂和蜂蜡的混合分散循环液，经输送装置从喷射口循环进入分散装置，与雾化口进入的虾青素溶液接触，循环往复，直至虾青素溶液输送完毕，最终得到虾青素、抗坏血酸棕榈酸酯、溶剂和蜂蜡的混合分散液11Kg，其中虾青素含量22.7％，溶剂残留0.13％，混合分散液中虾青素的平均粒径0.166μm。
将12.5Kg辛烯基琥珀酸淀粉钠溶解于60Kg水中，温度保持65℃，将上述混合分散液与辛烯基琥珀酸淀粉钠水溶液混合，500bar高压均质30min，得到乳状液，乳状液分散相平均粒径0.478μm。乳状液真空脱溶1小时，然后在喷雾造粒器中造粒，经流化床干燥，即得含虾青素9.0％的微胶囊，微胶囊的分散相平均粒径为0.481μm，微胶囊中虾青素颗 粒的平均粒径为0.168μm，产品中检测不到丙酮残留。
实施例3：
将2.5Kg虾青素结晶、1Kg BHT与400Kg二氯甲烷混合，升温至40℃，制成0.62％的虾青素溶液。10Kg玉米油经加热装置升温至90℃，经喷射口进入分散装置，虾青素溶液经雾化口进入分散装置，与呈喷射状态的玉米油接触混合，二氯甲烷迅速汽化，物料进入与分散装置连接的容器，容器保持负压状态，汽化的二氯甲烷经真空口排出，热交换器冷却到贮罐，可以循环使用。容器中得到虾青素、BHT、溶剂和玉米油的混合分散循环液，经输送装置从喷射口循环进入分散装置，与雾化口进入的虾青素溶液接触，循环往复，直至虾青素溶液输送完毕，最终得到虾青素、BHT、溶剂和玉米油的混合分散液13.5Kg，其中虾青素含量18.5％，溶剂残留0.15％，混合分散液中虾青素的平均粒径0.161μm。
将15Kg木质素磺酸钙溶解于35Kg水中，温度保持40℃，将上述混合分散液与木质素磺酸钙水溶液混合，800bar高压均质20min，得到乳状液，乳状液分散相平均粒径0.435μm。乳状液真空脱溶1小时，然后在喷雾造粒器中造粒，经流化床干燥，即得含虾青素7.2％的微胶囊，微胶囊的分散相平均粒径为0.441μm，微胶囊中虾青素颗粒的平均粒径为0.162μm，产品中检测不到二氯甲烷残留。
实施例4：
将虾青素结晶、生育酚、二氯甲烷按1:0.2:400的质量比混合，升温至40℃，制成0.25％的虾青素溶液，虾青素溶液以35Kg/h的流量经雾化口进入分散装置。菜籽油以0.35Kg/h的流量与循环分散液一起经加热装置升温至100℃，经喷射口进入分散装置与雾化态的虾青素溶液接触混合，二氯甲烷迅速汽化，物料进入与分散装置连接的容器，容器保持负压状态，汽化的二氯甲烷经真空口连续排出，热交换器冷却到贮罐，可以循环使用。容器中得到虾青素、生育酚、溶剂和菜籽油的混合分散循环液，经输送装置从喷射口循环进入分散装置，与雾化口进入的虾青素溶液接触混合，系统稳定后得到0.455Kg/h虾青素含量19.2％的混合分散液，虾青素在分散系统中的停留时间为10h，混合分散液打入中转釜，混合分散液中溶剂残留0.12％，虾青素的平均粒径0.102μm。
将木质素磺酸钠溶解于水中，配置木质素磺酸钠含量为35％的水溶液，温度保持40℃备用。将上述虾青素含量20％的混合分散液以0.455Kg/h的流量送入超重力旋转填充床打浆器中，同时将已配好的木质素磺酸钠水溶液以2.82Kg/h流量送入上述超重力旋转床打浆器中，得到流量约3.28Kg/h的乳状液，乳状液中分散相平均粒径0.236μm。将上述乳状液连续送入喷雾造粒器中造粒，经流化床干燥，即得含虾青素5.6％的微胶囊，微胶囊的分散相平均粒径为0.241μm，微胶囊中虾青素颗粒的平均粒径为0.109μm，产品中检测 不到二氯甲烷残留。
实施例5：
将虾青素结晶、茶多酚、氯仿按1:0.7:500的质量比混合，升温至40℃，制成0.2％的虾青素溶液，虾青素溶液以30Kg/h的流量经雾化口进入分散装置。巴西棕榈蜡以0.26Kg/h的流量与循环物料一起经加热装置升温至100℃，经喷射口进入分散装置与雾化态的虾青素溶液接触混合，氯仿迅速汽化，物料进入与分散装置连接的容器，容器保持负压状态，汽化的氯仿经真空口连续排出，热交换器冷却到贮罐，可以循环使用。容器中得到虾青素、生育酚、溶剂和巴西棕榈蜡的混合分散循环液，经输送装置从喷射口循环进入分散装置，与雾化口进入的虾青素溶液接触混合，系统稳定后得到0.36Kg/h虾青素含量16.6％的的混合分散液，虾青素在分散系统中的停留时间为15h，混合分散液打入中转釜，混合分散液中溶剂残留0.21％，虾青素的平均粒径0.115μm。
将辛烯基琥珀酸淀粉酯溶解于水中，配置辛烯基琥珀酸淀粉酯含量为24％的水溶液，温度保持40℃备用。将上述虾青素含量18.7％的混合分散液以0.36Kg/h的流量送入超重力旋转填充床打浆器中，同时将已配好的木质素磺酸钠水溶液以1.5Kg/h流量送入上述超重力旋转床打浆器中，得到流量约1.86Kg/h的乳状液，乳状液中分散相平均粒径0.214μm。将上述乳状液连续送入喷雾造粒器中造粒，经流化床干燥，即得含虾青素6.8％的微胶囊，微胶囊的分散相平均粒径为0.225μm，微胶囊中虾青素颗粒的平均粒径为0.120μm，产品中检测不到二氯甲烷残留。
对比例1：
将5Kg虾青素结晶、2.5Kg生育酚溶于400Kg二氯甲烷中，制成虾青素溶液。将20Kg明胶、10Kg麦芽糊精溶于80Kg水中，降温至40℃。将虾青素溶液缓缓滴加到水性相中，边滴加边剪切乳化脱溶，滴加完，脱除残留溶剂，然后在喷雾造粒器中造粒，流化床干燥，即得含虾青素11.0％的微胶囊，微胶囊中虾青素颗粒平均粒径为0.263μm，产品溶剂残留43ppm。
对比例2：
将5Kg虾青素结晶、2Kg抗坏血酸棕榈酸酯溶于400Kg丙酮中，制成虾青素溶液。将25Kg辛烯基琥珀酸淀粉钠、15Kg糊精溶于120Kg水中，温度保持65℃。将虾青素溶液缓缓滴加到水性相中，边滴加边剪切乳化脱溶，滴加完，脱除残留溶剂，然后在喷雾造粒器中造粒，流化床干燥，即得含虾青素9.1％的微胶囊，微胶囊中虾青素颗粒平均粒径为0.251μm，产品溶剂残留39ppm。
将实施例1、实施例2、实施例3、实施例4、实施例5、对比例1、对比例2制备得 到的虾青素微粒的加工稳定性进行对比。虾青素微粒与其他饲料原料混合、调质、膨化、制粒、烘干，测定烘干后饲料中虾青素的保留率，结果如下表1所示。
表1：不同虾青素微胶囊饲料加工保留率
Figure PCTCN2021090793-appb-000001
将实施例1、实施例2、实施例4、对比例1制备得到的虾青素微粒加入到商品饲料中，经膨化加工制成饲料A、饲料B、饲料C、饲料D，饲料A、B、C、D虾青素实测含量分别为50ppm、49ppm、51ppm、50ppm。分别用饲料A、B、C、D养殖虹鳟8周，对肌肉着色效果进行对比，结果如下表2所示。
表2：不同虾青素饲料对虹鳟8周肌肉着色的影响
组别 SalmoFan色卡值 肌肉红度(a*) 虾青素含量(mg/Kg)
A 28.57±1.93 16.55±1.63 1.69±0.60
B 28.98±1.93 17.86±1.46 1.82±0.31
C 29.31±1.54 18.17±1.33 1.87±0.42
D 26.16±1.46 11.47±1.45 1.15±0.36
实施例6：
将1.25Kg斑蝥黄结晶、0.25Kg乙氧基喹啉与500Kg氯仿混合，升温至65℃，制成0.25％的斑蝥黄溶液。12.5Kg氢化棕榈油经加热装置升温至100℃，经喷射口进入分散装置，斑蝥黄溶液经雾化口进入分散装置，与呈喷射状态的氢化棕榈油接触混合，氯仿迅速汽化，物料进入与分散装置连接的容器，容器保持负压状态，汽化的氯仿经真空口排出，热交换器冷却到贮罐，可以循环使用。容器中得到斑蝥黄、乙氧基喹啉、溶剂和氢化棕榈油的混合分散循环液，经输送装置从喷射口循环进入分散装置，与雾化口进入的斑蝥黄溶液接触，循环往复，直至斑蝥黄溶液输送完毕，最终得到斑蝥黄、乙氧基喹啉、溶剂和氢化棕榈油的混合分散液14Kg，其中斑蝥黄含量8.9％，溶剂残留0.23％，混合分散液中斑 蝥黄的平均粒径0.131μm。
将37.5Kg木质素磺酸钠溶解于62.5Kg水中，温度保持65℃，将上述混合分散液与木质素磺酸钠水溶液混合，高速剪切乳化30min，得到乳状液，乳状液分散相平均粒径0.355μm。乳状液真空脱溶1小时，然后在喷雾造粒器中造粒，经流化床干燥，即得含斑蝥黄2.0％的微胶囊，微胶囊的分散相平均粒径为0.362μm，微胶囊中斑蝥黄颗粒的平均粒径为0.133μm，产品中检测不到氯仿残留。
实施例7：
将番茄红素结晶、生育酚、二氯甲烷按1:0.2:800的质量比混合，升温至40℃，制成0.12％的番茄红素溶液，番茄红素溶液以20Kg/h的流量经雾化口进入分散装置。菜籽油以0.49Kg/h的流量与循环物料一起经加热装置升温至100℃，经喷射口进入分散装置与雾化态的番茄红素溶液接触混合，二氯甲烷迅速汽化，物料进入与分散装置连接的容器，容器保持负压状态，汽化的二氯甲烷经真空口连续排出，热交换器冷却到贮罐，可以循环使用。容器中得到番茄红素、生育酚、溶剂和菜籽油的混合分散循环液，经输送装置从喷射口循环进入分散装置，与雾化口进入的番茄红素溶液接触混合，系统稳定后得到0.52Kg/h番茄红素含量4.8％的的混合分散液，番茄红素在分散系统中的停留时间为8h，混合分散液打入中转釜，混合分散液中溶剂残留0.11％，番茄红素的平均粒径0.107μm。
将木质素磺酸钠溶解于水中，配置木质素磺酸钠含量为35％的水溶液，温度保持40℃备用。将上述番茄红素含量4.8％的混合分散液以0.52Kg/h的流量送入超重力旋转填充床打浆器中，同时将已配好的木质素磺酸钠水溶液以3.3Kg/h流量送入上述超重力旋转床打浆器中，得到流量约3.8Kg/h的乳状液，乳状液中分散相平均粒径0.286μm。将上述乳状液连续送入喷雾造粒器中造粒，经流化床干燥，即得含番茄红素1.2％的微胶囊，微胶囊的分散相平均粒径为0.292μm，微胶囊中番茄红素颗粒的平均粒径为0.111μm，产品中检测不到二氯甲烷残留。
实施例8：
β-胡萝卜素结晶、抗坏血酸棕榈酸酯、二氯甲烷按1:0.4:1600的质量比混合，升温至40℃，制成0.06％的β-胡萝卜素溶液，β-胡萝卜素溶液以25Kg/h的流量经雾化口进入分散装置。棕榈油以0.59Kg/h的流量与循环物料一起经加热装置升温至100℃，经喷射口进入分散装置与雾化态的β-胡萝卜素溶液接触混合，二氯甲烷迅速汽化，物料进入与分散装置连接的容器，容器保持负压状态，汽化的二氯甲烷经真空口连续排出，热交换器冷却到贮罐，可以循环使用。容器中得到β-胡萝卜素、生育酚、溶剂和棕榈油的混合分散循环液，经输送装置从喷射口循环进入分散装置，与雾化口进入的β-胡萝卜素溶液接触混合，系统 稳定后得到0.65Kg/hβ-胡萝卜素含量2.4％的的混合分散液，β-胡萝卜素在分散系统中的停留时间为7h，混合分散液打入中转釜，混合分散液中溶剂残留0.12％，β-胡萝卜素的平均粒径0.085μm。
将明胶溶解于水中，配置明胶含量为21.4％的水溶液，温度保持40℃备用。将上述β-胡萝卜素含量2.4％的混合分散液以0.65Kg/h的流量送入超重力旋转填充床打浆器中，同时将已配好的木质素磺酸钠水溶液以3.65Kg/h流量送入上述超重力旋转床打浆器中，得到流量约4.3Kg/小时的乳状液，乳状液分散相平均粒径0.332μm。将上述乳状液连续送入喷雾造粒器中造粒，经流化床干燥，即得含β-胡萝卜素1.0％的微胶囊，微胶囊的分散相平均粒径为0.343μm，微胶囊中β-胡萝卜素颗粒的平均粒径为0.089μm，产品中检测不到二氯甲烷残留。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本申请的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本申请构思的前提下，还可以做出若干变形和改进，这些都属于本申请的保护范围。因此，本申请专利的保护范围应以所附权利要求为准。

Claims (21)

  1. 一种稳定、高生物利用度的类胡萝卜素微胶囊的制备方法，所述方法包括如下步骤：
    a)将类胡萝卜素结晶与有机溶剂混合，溶解，得到类胡萝卜素溶液；
    b)将所述类胡萝卜素溶液与热油脂通入分散系统，使类胡萝卜素充分分散至所述热油脂中，并使有机溶剂汽化，得到类胡萝卜素混合分散液；
    c)将所得类胡萝卜素混合分散液与保护性胶体的水溶液混合，进行乳化得到乳状液；
    d)将所述乳状液进行喷雾造粒，然后干燥，得到类胡萝卜素微胶囊。
  2. 根据权利要求1所述的类胡萝卜素微胶囊的制备方法，其中，步骤b)所述分散系统包括分散装置、连接所述分散装置的容器、输送装置和加热装置，所述分散装置用于步骤a)得到的所述类胡萝卜素溶液与所述热油脂或循环物料接触，使类胡萝卜素充分分散到所述热油脂中；所述输送装置用于将物料在所述分散系统中传输；所述加热装置用于将油脂或循环物料加热为液态。
  3. 根据权利要求2所述的类胡萝卜素微胶囊的制备方法，其中，所述分散装置包括依次连接的接触段、收缩段及扩张段；
    所述接触段设置有喷射口和雾化口，所述喷射口将加热的液态热油脂或循环物料经所述喷射口引入所述接触段；所述雾化口将步骤a)得到的类胡萝卜素溶液经所述雾化口形成微小的雾滴，引入所述接触段，与呈喷射状的液态热油脂或循环物料接触混合，使所述类胡萝卜素溶液中的有机溶剂汽化，形成类胡萝卜素颗粒并分散在所述热油脂中；
    所述收缩段进一步将所述接触段形成的类胡萝卜素雾滴与油脂混合，蒸发所述有机溶剂，进入所述扩张段，再进入与所述分散装置连接的所述容器中。
  4. 根据权利要求3所述的类胡萝卜素微胶囊的制备方法，其中，所述连接分散装置的容器还包括真空口，将汽化的所述有机溶剂通过所述真空口排出所述容器。
  5. 根据权利要求2所述的类胡萝卜素微胶囊的制备方法，其中，所述分散系统为连续操作或间歇操作。
  6. 根据权利要求2所述的类胡萝卜素微胶囊的制备方法，其中，所述物料在所述分散系统中的停留时间≤20h。
  7. 根据权利要求1所述的类胡萝卜素微胶囊的制备方法，其中，所述热油脂的温度为60℃-100℃。
  8. 根据权利要求1所述的类胡萝卜素微胶囊的制备方法，其中，步骤b)中仅将所述类胡萝卜素溶液中的部分所述有机溶剂汽化脱除，所述类胡萝卜素混合分散液中的残留所述有机溶剂的含量低于1％。
  9. 根据权利要求1所述的类胡萝卜素微胶囊的制备方法，其中，步骤c)还包括：进行乳化后脱除所述乳状液中的残留有机溶剂的步骤。
  10. 根据权利要求1所述的类胡萝卜素微胶囊的制备方法，其中，类胡萝卜素以部分溶解及颗粒分散的状态存在于步骤b)得到的所述类胡萝卜素混合分散液中；所述类胡萝卜混合分散液中的类胡萝卜素颗粒的平均粒径为0.05μm-0.2μm。
  11. 根据权利要求1所述的类胡萝卜素微胶囊的制备方法，其中，所述步骤b)中，所述热油脂与类胡萝卜素结晶的质量比为0.7:1-20:1。
  12. 根据权利要求1-11任一项所述的类胡萝卜素微胶囊的制备方法，其中，步骤c)所述的乳化方法为高压均质乳化、在线管道式高剪切乳化、超重力乳化和静态混合中的一种或多种。
  13. 根据权利要求1-11任一项所述的类胡萝卜素微胶囊的制备方法，其中，所述保护性胶体选自明胶、辛烯基琥珀酸淀粉酯、阿拉伯胶、木质素磺酸钠、木质素磺酸钙、聚丙烯酸钠和羧甲基纤维素钠中的一种或多种。
  14. 根据权利要求1-11任一项所述的类胡萝卜素微胶囊的制备方法，其中，经过步骤c)所述的乳化，所述混合分散液分散在所述保护性胶体中，分散相平均粒径小于0.7μm，所述分散相包含至少一种类胡萝卜素颗粒、至少一种油脂，所述类胡萝卜素颗粒以纳米分散的形式被包裹在所述油脂中。
  15. 根据权利要求1-11任一项所述的类胡萝卜素微胶囊的制备方法，其中，步骤a)的所述有机溶剂选自氯仿、二氯甲烷、乙酸乙酯、乙酸丙酯、丙酮和丙醇中的一种或多种。
  16. 根据权利要求1-11任一项所述的类胡萝卜素微胶囊的制备方法，其中，步骤a)中所述有机溶剂与所述类胡萝卜素结晶的质量比为100:1-2000:1。
  17. 根据权利要求1-11任一项所述的类胡萝卜素微胶囊的制备方法，其中，所述类胡萝卜素溶液中添加有抗氧化剂，所述抗氧化剂选自TBHQ、VC-棕榈酸酯、生育酚、迷迭香、茶多酚、没食子酸丙酯、BHT、抗坏血酸钠、抗坏血酸和乙氧基喹啉中的一种或多种；和/或，所述抗氧化剂与所述类胡萝卜素结晶的质量比为0.1:1-3:1。
  18. 根据权利要求1-11任一项所述的类胡萝卜素微胶囊的制备方法，其中，所述步骤b)中的所述热油脂为生理上可接受的油脂，其中所述油脂选自蜡类、植物油脂和氢化植物油脂中的一种或多种。
  19. 根据权利要求18所述的类胡萝卜素微胶囊的制备方法，其中，所述蜡类选自蜂蜡、巴西棕榈蜡、小烛树蜡、微晶蜡、褐煤酸酯蜡、稻芽油蜡、鲸蜡、羊毛脂蜡、西门德木蜡、萨索尔蜡和日本蜡中的一种或多种；和/或，所述植物油脂选自玉米油、大豆油、葵花籽油、 橄榄油、椰子油、菜籽油、棉籽油、棕榈油、棕榈硬脂和可可脂中的一种或多种；和/或，所述氢化植物油脂选自氢化棉籽油、氢化棕榈油和氢化大豆油中的一种或多种。
  20. 根据权利要求1-11任一项所述的类胡萝卜素微胶囊的制备方法，其中，步骤a)的所述类胡萝卜素结晶选自β-胡萝卜素、叶黄素、玉米黄质、番茄红素、角黄素、虾青素、辣椒红素、柠檬黄素、β-阿朴-8’-胡萝卜素醛、β-阿朴-8’-胡萝卜素酸乙酯中的一种或多种。
  21. 一种根据权利要求1-20任一项所述类胡萝卜素微胶囊的制备方法制备得到的稳定、高生物利用度的类胡萝卜素微胶囊，其特征在于，所述类胡萝卜素微胶囊的分散相分散在所述保护性胶体中，分散相平均粒径小于0.7μm，所述分散相包含至少一种类胡萝卜素颗粒、至少一种油脂，所述类胡萝卜素颗粒以纳米分散的形式被包裹在所述油脂中。
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