WO2020187084A1 - 一种高生物利用度高稳定性的类胡萝卜素制剂的制备方法 - Google Patents

一种高生物利用度高稳定性的类胡萝卜素制剂的制备方法 Download PDF

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WO2020187084A1
WO2020187084A1 PCT/CN2020/078522 CN2020078522W WO2020187084A1 WO 2020187084 A1 WO2020187084 A1 WO 2020187084A1 CN 2020078522 W CN2020078522 W CN 2020078522W WO 2020187084 A1 WO2020187084 A1 WO 2020187084A1
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grinding
water
preparation
carotenoid
particle size
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PCT/CN2020/078522
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English (en)
French (fr)
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许新德
周迪
谢恬
叶双明
王胜南
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浙江医药股份有限公司新昌制药厂
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Priority to EP20773726.3A priority Critical patent/EP3943075A4/en
Priority to US17/440,198 priority patent/US20220160653A1/en
Publication of WO2020187084A1 publication Critical patent/WO2020187084A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
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    • A—HUMAN NECESSITIES
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    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/035—Organic compounds containing oxygen as heteroatom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A23L5/40—Colouring or decolouring of foods
    • A23L5/42—Addition of dyes or pigments, e.g. in combination with optical brighteners
    • A23L5/43—Addition of dyes or pigments, e.g. in combination with optical brighteners using naturally occurring organic dyes or pigments, their artificial duplicates or their derivatives
    • A23L5/44—Addition of dyes or pigments, e.g. in combination with optical brighteners using naturally occurring organic dyes or pigments, their artificial duplicates or their derivatives using carotenoids or xanthophylls
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/40—Shaping or working of foodstuffs characterised by the products free-flowing powder or instant powder, i.e. powder which is reconstituted rapidly when liquid is added
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • A—HUMAN NECESSITIES
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    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1658—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5052—Proteins, e.g. albumin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
    • B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
    • B02C23/00—Auxiliary methods or auxiliary devices or accessories specially adapted for crushing or disintegrating not provided for in preceding groups or not specially adapted to apparatus covered by a single preceding group
    • B02C23/18—Adding fluid, other than for crushing or disintegrating by fluid energy
    • B02C23/36—Adding fluid, other than for crushing or disintegrating by fluid energy the crushing or disintegrating zone being submerged in liquid
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/70—Fixation, conservation, or encapsulation of flavouring agents
    • A23L27/72—Encapsulation

Definitions

  • the invention relates to a method for producing a carotenoid preparation by a direct grinding method.
  • the obtained preparation has good stability and high bioavailability.
  • the preparation can be a water-soluble suspension. According to needs, the water-soluble suspension can also be granulated to obtain water-soluble It belongs to the field of pharmaceutical preparations.
  • Carotenoids are widely present in nature. In 1831, Wachenroder crystallized and separated carbohydrate pigments from carrot roots for the first time, and named them “carotene.” Later, Berzelius extracted yellow polarities from autumn leaves. Pigment, and named “lutein”; with the development of biophysical technology, people separated a series of natural pigments through chromatography and named them “carotenoids”. They have the same chemical structure characteristics. The molecular center of the polyisoprene long chain is polyene bond, and many derivatives are produced through the end cyclization, oxygen addition or bond rotation and isomerization. Currently, there are about 600 known members of carotenoids.
  • Carotenoids belong to terpenoid compounds, which are the general term for two types of pigments, carotene and Xanthophylls. Hydrocarbon carotenoids that do not contain oxygen atoms in the molecule are called carotenes; derivatives and esters that contain oxygen functional groups (such as hydroxyl, epoxy, methoxy, ketone, hydroxyl, etc.) in the molecule It is called the lutein family.
  • carotenoids there are hundreds of carotenoids in nature, but there are mainly six more common and relatively large ones. They are ⁇ -carotene, astaxanthin, cantharidin, lutein, and zeaxanthin. And lycopene, etc. With the development of biotechnology and synthesis technology, many of these six carotenoids have multiple sources. For example, beta-carotene can be fully synthesized, and can be obtained through fermentation or culture of Dunaliella salina, or from Extracted from natural products such as palm oil; lycopene can be derived from natural sources such as extracted or fermented from tomatoes, or it can be fully synthesized; among these carotenoids, lutein is an exception. Due to structural asymmetry, currently Only by extracting from plants, and not high-cost synthesis.
  • carotenoids are all similar in molecular structure. They are a type of hydrocarbons and their oxidized derivatives. They are composed of 8 isoprenoid units, but there are slight differences in the two terminal six-membered rings. .
  • the presence of multiple conjugated double bond chromophores in the molecular structure of carotenoids not only endows it with a unique absorption region (blue region) in the ultraviolet-visible region, so its crystal or solution has a very brilliant red under visible light. , Orange or yellow, due to the different density, the displayed color has a certain change.
  • Carotenoids have long been regarded as a kind of pigments. Fallen leaves and various variegated animals in nature give humans an unparalleled beauty. At the same time, these conjugated double bonds also make carotenoids a good free radical quencher, which has strong antioxidant activity and can effectively block the chain free radical reaction in the cell, so it has a variety of unique and important The physiological functions.
  • beta-carotene which is a good provitamin A. According to the amount of vitamin A in the body, beta-carotene can be automatically decomposed to supplement the deficiency of vitamin A.
  • Lutein and zeaxanthin are isomers. The only difference is the position of a double bond on one of the six-membered ring ends. They are the only carotenoid that exists in the retina of human eyes. They are selective The ground is deposited in the macular area and the entire retina. The density around the fovea of the macula is the highest, and the peripheral part of the retina gradually decreases. These macular pigments can effectively prevent oxidation on the retina and have an important protective effect on the retina.
  • Lycopene has a good effect on the prevention and treatment of prostate diseases. Astaxanthin also has important anti-tumor and cancer prevention effects. This is why many epidemiological studies have confirmed that regular and regular consumption of fruits and vegetables containing carotenoids can reduce the risk of chronic diseases, including cardiovascular diseases, and has the beneficial effect of preventing cancer.
  • carotenoid molecules are encapsulated in water-soluble colloids, which can not only improve the dissolution and dispersion characteristics of carotenoid molecules, and be soluble in water, but also effectively isolate the disadvantages of oxygen and light.
  • the contact between the factor and the carotenoid molecules enhances its stability.
  • the carotenoid molecules can be dispersed in the form of nanometers or micrometers, it is beneficial to absorption and utilization in the human body and improves its bioavailability.
  • the preparation process of carotenoid microcapsule preparations generally involves several steps: one is to dissolve water-soluble colloids such as gelatin, modified starch, and fillers such as sucrose and maltodextrin in water to obtain an aqueous phase; the other is to dissolve carotenoid crystals It is dissolved, melted, or dispersed with antioxidants in some way to form an oil phase; third, the water phase and the oil phase are fully mixed to form an oil-in-water dispersible emulsion. According to needs, the dispersible emulsion can be granulated to obtain carotenoid microcapsule dry powder or particles.
  • the most difficult one is the preparation of the oil phase, which is mainly due to the poor solubility of carotenoid crystals, high melting point, easy degradation at high temperatures, and isomerization and denaturation.
  • there are currently three conventional methods for preparing carotenoid oil phase one is to dissolve carotenoid in an organic solvent to form an oil phase, then mix with the water phase to emulsify, and then remove the organic solvent.
  • the removal of organic solvents will not be complete, especially in the emulsion due to the presence of emulsifiers, organic solvents are more difficult to remove cleanly.
  • some all-trans carotenoids will be different.
  • the second is to dissolve carotenoid crystals at a high temperature of about 180 °C to obtain an oil phase.
  • a significant disadvantage of this method is that at such high temperatures, a large part of the carotenoid molecules will degrade or undergo isomerization from all-trans to cis, greatly reducing its biological activity, and the final carotenoid solution The color system will change; the third is to mix carotenoid crystals with vegetable oil and then grind.
  • the advantage of this method is that no organic solvents are used in the process, there are no safety concerns, and the carotenoid molecules are not subjected to high temperature processes.
  • the all-trans content is high, but an obvious shortcoming in this respect is that it is difficult to grind carotenoid crystals to a sufficient fineness by conventional methods, resulting in low bioavailability of the final product.
  • organic solvents are used to dissolve carotenoids to obtain an oil phase, which is mixed with water to emulsify, and the organic solvent is removed or not removed to obtain a carotenoid microcapsule preparation.
  • US20110207831 introduces the preparation of carotenoid microcapsule preparations by the melting method. Due to the degradation and isomerization of some carotenoids in the high temperature process, the color of the final product is yellowish and the biological activity is reduced.
  • US20080220071 discloses a water-soluble suspension containing carotenoids, in which in addition to the solvent method, the oil phase is prepared by grinding with a grinder, but in this application, in order to achieve the required fineness, the oil phase must be processed Many long-term cycles are detrimental to the energy consumption and the stability of carotenoid molecules in the production process.
  • US20100120922 discloses a method for producing water-soluble carotenoid microcapsule solution by grinding method.
  • a large amount of alcoholic solvent such as glycerin has to be added to the formula , Propylene glycol, etc. in order to reduce the viscosity of the oil phase during grinding, which is unfavorable to the increase in the content of effective ingredients in the final product and its stability.
  • CN109156827 mentions a method for preparing red carotene preparations.
  • a nano-grinding machine is used to grind carotenoid colloidal solution.
  • circular grinding is required, and the grinding time is very long
  • the pressure is very high.
  • US20080207775 describes the preparation of a water-soluble carotenoid microcapsule solution. After mixing part of the water phase and carotenoid crystals, it is ground with a grinder, and then part of the embedded wall material, filler, Antioxidants, etc. form secondary embedding. In this process, due to only one grinding, the carotenoid particle size in the final product is relatively coarse, reaching 0.6m, which is not enough to improve its bioavailability in the human body.
  • the present invention provides a method for preparing a water-dispersible carotenoid microcapsule preparation with high bioavailability and high stability.
  • the preparation method includes the following steps: a) dissolving a part of a water-soluble colloid and a filling substance in water; To form an aqueous phase; b) add carotenoid crystals to the aqueous phase and stir and disperse to form a dispersion; c) put the dispersion into the first-stage grinder for the first grinding to form a Level grinding liquid; d) Adding the remaining water-soluble colloid and filler to the first level grinding liquid, and then entering the second level grinding machine for a second grinding to obtain the second level grinding liquid; e) After drying the water in the secondary grinding solution, dry carotenoid powder or particles are obtained.
  • the water in the ground nano-scale carotenoid dispersion can be dried to obtain carotenoid microcapsule dry powder/particles.
  • Conventional drying methods include spray drying, spray condensation-
  • the carotenoid is ⁇ -carotene, lutein, lycopene, cantharidin, zeaxanthin or astaxanthin;
  • the water-soluble The colloid is one or more of modified starch, gelatin, casein, acacia, and soy protein isolate;
  • the filling material is one or more of sucrose, maltodextrin, and syrup.
  • the grinding media in the first-stage grinder and the second-stage grinder are food-grade sanitary materials, including 306L stainless steel, tungsten carbide, and zirconia , Yttrium stabilized zirconia beads. More preferably, the bead particle size of the grinding medium in the first-stage grinder is between 0.6-0.8mm; the bead particle size of the grinding medium in the second-stage grinder is between 0.3-0.4mm between.
  • the addition amount of the water-soluble colloid in step a) is 5-95wt.% of the total water-soluble colloid, and the addition amount of the filler is the total filler. 5-95wt.% of substance.
  • the solid content of the dispersion in step b) is between 5-50 wt.%.
  • the first grinding is performed in step c) until the particle size of the carotenoid crystal particles is 0.5-1.5 ⁇ m, and the grinding is stopped to obtain a first-level grinding liquid.
  • the amount of water-soluble colloid added for the second time in step d) is 95-5wt.% of the total amount of water-soluble colloid.
  • the added amount of the second filling material in step d) is 95%-5wt.% of the total filling material in the formula.
  • the second grinding is performed in step d) until the particle size of the carotenoid crystal particles is 150-600 nm, and the grinding is stopped to obtain a secondary grinding liquid.
  • an antioxidant is added, and the antioxidant is one of synthetic tocopherol, natural vitamin E, ascorbic acid, and ascorbyl palmitate. Several kinds. More preferably, the added amount of the antioxidant is 1.25%-5.0wt.% of the mass of the final product.
  • the carotenoid content in the carotenoid water-dispersed microcapsule preparation is 1.0-30 wt. .%between.
  • the preparation method of the present invention is to dissolve part of the water-soluble colloid and filler in water to form an aqueous phase, disperse the carotenoid crystals in the water phase and pass the primary grinding, and then add the remaining water-soluble colloid and filler. After the second level of grinding, a carotenoid nano-dispersed water-soluble suspension is obtained.
  • the water-soluble suspension can be spray-dried or spray-condensed to obtain carotenoid microcapsule dry powder or particles.
  • the use of a two-stage grinder for grinding in the process can effectively complete the nano-level dispersion of carotenoids in a short time.
  • the particle size of the grinding media balls in the two-stage grinder is different, and the grinding media ball particles in the first-stage grinder The diameter is coarse (the ball size is between 0.6-0.8mm) to achieve the initial grinding effect.
  • the particle size is about 1 ⁇ m; the second level of grinding media The diameter is between 0.3-0.4mm), and is finely milled to finally achieve nano-scale dispersion.
  • the particle size is generally below 500nm, more preferably 200-300nm.
  • the combined application of two-stage ball milling can achieve the effect of nano-dispersion of carotenoids in the final product in a short time, and the grinding time is greatly reduced.
  • the conventional single-stage circular grinding is more than 6 hours, shortened to 0.5-2.0 hours.
  • particle size is about 1 ⁇ m
  • the particle size is already small, reaching the micron level.
  • the supplementary solid matter has little effect on the viscosity of the grinding solution.
  • the particle size can further achieve the effect of nano-level dispersion.
  • the requirements for solid content (or viscosity) during grinding are different.
  • the carotenoid concentration in the final product is low (the input amount of carotenoid crystals is small)
  • the solids concentration can be higher during one grinding.
  • the solid content in the grinding liquid is required to be lower.
  • the carotenoid content in the final product is about 1%
  • 95% of the total amount of water-soluble colloids and fillers can be input in one grinding, and the solid content can reach 50%.
  • the carotenoid content in the final product reaches 30%, the solid content can only be about 5% during one grinding. With this lower solid content, the lower viscosity during one grinding can be ensured to achieve Better grinding effect.
  • the addition of water-soluble colloids in batches also has an unexpected effect, that is, it can make the carotenoids in the final product form a secondary embedding, and greatly enhance the stability of the carotenoid content in the final product.
  • the main reason is that when the water-soluble colloid and carotenoid crystals are ground together for the first time, the carotenoid crystals are continuously formed into micronized powder under the action of the grinding media balls, and dispersed in the water-soluble colloidal solution to form micron-level droplets. Embedding for the first time. Before the second grinding, add water-soluble colloid. The micron-sized dispersed droplets are continuously broken and recombined during grinding to form new nano-level droplets. In this process, the added water-soluble colloid is re-introduced in these The surface of the nanometer droplet is wrapped to form a second embedding.
  • the secondary embedding has a positive effect on the stability and pressure resistance of the final product.
  • the said grinder is a ball mill, sand mill, etc. that can be purchased on the market.
  • the main structure is a hollow cylinder placed horizontally and rotating around a horizontal axis.
  • the cylinder is filled with grinding media and materials to be ground.
  • the movement of the grinding medium causes the materials to be crushed by squeezing, friction, impact, grinding and shearing.
  • the grinding medium in the grinder used in the application process is food-grade sanitary materials, including 306L stainless steel, or tungsten carbide, or zirconia, etc., preferably yttrium stabilized zirconia beads.
  • Water-soluble colloids are conventional colloidal substances that are available on the market and have an emulsification stabilizing effect, including one or more of modified starch, gelatin, casein, acacia, and soy protein isolate.
  • the filling material includes one or more of sucrose, maltodextrin, and syrup.
  • the water-soluble colloid and filling material added for the first time account for 5%-95% of the total water-soluble colloid and filling material in the formula respectively.
  • the solid content before the first grinding is between 5-50%.
  • the particle size of the grinding media balls in the grinder is between 0.6-0.8mm.
  • the remaining water-soluble colloid and filler material After taking out the micron-level dispersion obtained from the first grinding, add the remaining water-soluble colloid and filler material, the remaining water-soluble colloid and filler material respectively account for 95%-5% of the total water-soluble colloid and filler mass in the formula , Into the second level of grinding machine grinding.
  • the particle size of the grinding media balls in the grinder is between 0.3-0.4mm.
  • antioxidants can be added to the formula, such as synthetic tocopherol, natural vitamin E, ascorbic acid, ascorbyl palmitate, BHT, etc.
  • the production process of carotenoid preparations obtained by this "second grinding and second embedding" process is easy to operate, short grinding time, low energy consumption, and the droplets in the final product are dispersed at nanometer level, and the dispersion is uniform, and the particle size spans It is small, and because the carotenoid molecules are embedded twice, it has good stability and is easy to be compressed into tablets. Compared with the previous process, this process has significant advantages.
  • modified starch (PG 2000, purchased from Ingredion) and 25g of sucrose, completely dissolve it in 580ml of hot water at 50°C to form a water-soluble colloidal solution.
  • beta-carotene crystals and synthesize 65g of tocopherols, add them to the above colloidal solution (solid content 50%), and perform the first grinding in a sand mill (Sunller Machine) to grind the medium yttrium stabilized zirconia beads particle size Between 0.6-0.8mm, after grinding for 0.3hr, sampling and testing, the beta-carotene particles have a particle size of 1.5 ⁇ m, stop grinding to obtain a first-grade grinding liquid.
  • the secondary grinding fluid was spray-dried to remove water content to obtain dry powder of lutein microcapsules.
  • the content of lutein is 6.43%.
  • the storage stability of this dry powder of lutein is very good.
  • the stability retention rate data is shown in Table 2. .
  • the secondary grinding fluid is spray-starch stream instantaneous forming method to remove the water in it to obtain cantharidin microcapsule particles, in which the content of cantharidin is 11.56%, the storage stability of cantharidin particles is very good, and its stability retention rate
  • Table 2 The data are shown in Table 2.
  • the water in the secondary grinding liquid is removed by spray-starch flow instant molding method to obtain lycopene microcapsule particles, in which the lycopene content is 29.69%.
  • the storage stability of the cantharidin particles is very good, and its stability
  • the retention rate data is shown in Table 2.
  • Table 1 The particle size of cantharidin particles in the aqueous dispersion obtained by sampling at different time points
  • This grinding liquid has good water dispersibility, and it is pinkish and opaque after being dispersed in water.
  • the water in the grinding solution was removed by the spray-starch flow instant molding method to obtain cantharidin microcapsule particles, in which the cantharidin content was 11.24%.
  • the storage stability retention rate data of the cantharidin particles are shown in Table 2.
  • the above-mentioned first-level grinding liquid is directly fed into the second sand mill (Sunller Machine) for the second grinding.
  • the particle size of the yttrium-stabilized zirconia beads in the grinding medium is between 0.3-0.4mm. After grinding for 1.0hr, samples are taken for detection. The penicillin particles have a particle size of 478 nm, and the grinding is stopped to obtain a secondary grinding liquid.
  • the secondary grinding solution was spray-dried to remove water content to obtain astaxanthin microcapsule dry powder, in which the astaxanthin content was 6.35%, and the stability retention rate data are shown in Table 2.
  • the coating wall material and the filling material are added at one time, which greatly increases the solid content in the grinding liquid, thereby increasing its viscosity. It takes 6.0 hours of grinding to reduce the particle size of carotenoid particles in the grinding solution to below 500 nm, while the secondary grinding in the present invention can reduce the particle size to about 200 nm in only 2.0 hours. Moreover, adding the coated wall material in batches not only reduces the viscosity during grinding, improves the grinding efficiency, but also has the effect of secondary embedding, which greatly improves the stability of carotenoids in the final product formulation. 6 months In the accelerated stability test, its content retention rate is increasing.

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Abstract

一种高生物利用度高稳定性类胡萝卜素制剂的制备方法，包括步骤：a)将水溶性胶体和填充物质的一部分溶解于水中，形成水相；b)将类胡萝卜素晶体加入到水相中搅拌后分散，形成分散液；c)将分散液进入第一级研磨剂中进行第一次研磨，形成一级研磨液；d)向一级研磨液中补加剩余的水溶性胶体和填充物质，进入第二研磨机中进行第二次研磨，得到二级研磨液；e)将二级研磨液中水分干燥，得到类胡萝卜素干粉或微粒。

Description

一种高生物利用度高稳定性的类胡萝卜素制剂的制备方法 技术领域
本发明涉及通过直接研磨法生产类胡萝卜素制剂的方法，得到的制剂稳定性好，生物利用度高，制剂可以是水溶性悬浮液，根据需要，也可将此水溶性悬浮液制粒得到水溶性干粉或微粒，属于药物制剂领域。
技术背景
类胡萝卜素在自然界中广泛存在，1831年，Wachenroder从胡萝卜根中首次结晶分离出碳水化合物类的色素，并以“胡萝卜素”命名；之后，Berzelius从秋天的叶片中分离提取出黄色的极性色素，并命名为“叶黄素”；随着生物物理技术的发展，人们通过色谱方法分离出一系列的天然色素，并命名为“类胡萝卜素”。它们具有共同的化学结构特征，分子中心都是多烯键的聚异戊二烯长链，通过末端的环化、氧的加入或键的旋转及异构化等方式产生出许多衍生物。目前，己知的类胡萝卜素成员大概有600多种。
类胡萝卜素(Carotenoids)属于类萜化合物，是胡萝卜素(Carotene)和叶黄素(Xanthophylls)两大类色素的总称。分子中不含有氧原子的碳氢族类胡萝卜素称为胡萝卜素族；分子中含有氧功能团(如羟基、环氧基、 甲氧基、酮基、羟基等)的衍生物及其酯类则称为叶黄素族。
自然界存在的类胡萝卜素有数百种之多，但比较常见且数量相对较大的主要有六种，它们分别是β-胡萝卜素、虾青素、斑蝥黄素、叶黄素、玉米黄质和番茄红素等。随着生物技术和合成技术的发展，这六大类胡萝卜素中许多种类又存在着多种来源，如beta-胡萝卜素可以是全合成，又可通过发酵法或养殖盐藻得到，还可从天然物如棕榈油中提取；番茄红素可以是天然来源如从番茄中提取或发酵得到，也可是全合成的；在这些类胡萝卜素中叶黄素是个例外，由于结构上的不对称性，目前只有通过从植物中提取，而不会高成本地合成。
这六种类胡萝卜素在分子结构上都较为相似，是一类碳氢化合物及其氧化衍生物，它们由8个类异戊二烯单位组成，只是在两个末端六元环上存在细微的差别。类胡萝卜素分子结构中存在的多个共轭双键发色基团不仅赋予了其在紫外－可见光区有着独特的吸收区(蓝光区)，因而其结晶或溶液在可见光下具有十分绚丽的红、橙或黄色，因浓度的不同，显示出的颜色有一定的变化。类胡萝卜素长期被认为是一类色素，自然界中秋天的落叶和各种斑谰色彩的动物给人类以无与伦比的美感。同时这些共轭双键还使得类胡萝卜素成为良好的自由基猝灭剂，具有很强的抗氧化活性，能有效地阻断细胞内的链式自由基反应，从而具有多种独特而又重要的生理功能。
类胡萝卜素中最广泛而要重要的是beta-胡萝卜素，它是良好的维生素A原根据体内维生素A量的多少，beta-胡萝卜素可自动分解而补充维生素A的不足。叶黄素和玉米黄质是同分异构体，其唯一的区别 在于其中一个六元环端链上一个双键的位置不同，它们是唯一存在于人类眼视网膜上的一种类胡萝卜素，它们选择性地沉积在黄斑区和整个视网膜，以黄斑的中心凹周围密度为最高，视网膜周边部分逐渐减少。这些黄斑色素能有效地防止视网膜上面氧化反应的发生，对视网膜有重要的保护作用。番茄红素对前列腺疾病的预防和治疗有很好的作用。虾青素也有重要的抗肿瘤和预防癌症的作用等。这就是为什么许多流行病学研究证实，经常和有规律地消费含类胡萝卜素的水果和蔬菜可减少慢性疾病，包括心血管疾病的危险，同时具有预防癌症的有益效果。
因此，营养学家极力推荐添加、预防性地摄取抗氧化剂维生素和类胡萝卜素，食物和药物市场因而为消费者提供大量此类“细胞保护剂”。
但由于类胡萝卜素独特的分子结构特征使得它们溶解性很差，在水中根本不溶，在油中溶解度也很小，这也导致类胡萝卜素晶体在人体中生物利用度很差，很难被吸收利用，而且其分子结构中存在着很多双键，在空气中，以及遇热、光等很容易被氧化降解，稳定性差。为了达到提高其稳定性和生物利用度的目的，一个常规的方法就是将类胡萝卜素晶体制备成稳定性好，水溶性佳，生物利用率高的制剂产品，特别是水溶性悬浮液，或微胶囊干粉/微粒，在这些制剂产品中，类胡萝卜分子被包裹在水溶性胶体中，不仅能改善类胡萝卜素分子的溶解分散特性，在水中可溶，而且能有效地隔绝了氧气、光等不利因子与类胡萝卜素分子的接触，增强其稳定性，另外由于类胡萝卜素分 子能以纳米或微米形式分散，有利于在人体中吸收利用，提高了其生物利用率。
类胡萝卜微胶囊制剂制备过程中一般涉及几个步骤：一是将水溶性胶体如明胶、变性淀粉，与填充物如蔗糖、麦芽糊精等溶解于水中得水相；二是将类胡萝卜素晶体与抗氧化剂等通过某种方式或溶解，或熔融，或分散以形成油相；三是将水相与油相充分混合，形成水包油型分散性乳液。根据需要，可以将此分散性乳液进行造粒得类胡萝卜素微胶囊干粉或微粒。在这些步骤中，难度最大的是油相的制备，主要是因为类胡萝卜素晶体溶解性差，熔点高，高温下易降解及异构化变性的特性造成的。虽然如此，目前仍有三种常规方法制备类胡萝卜素油相：一是将类胡萝卜素溶解于有机溶剂中形成油相，然后与水相混合乳化，再将有机溶剂脱除。但有机溶剂的脱除不会很完全，特别是在乳液中由于乳化剂的存在，有机溶剂更难脱除干净，另外类胡萝卜素溶解过程中，也会有部分全反式类胡萝卜素会异构化为顺式异构体，从而降低了其生物活性；二是将类胡萝卜素晶体于180℃左右高温下溶解得油相。此方法一个显著的缺点就是在如此高温下，很大一部分类胡萝卜素分子会降解，或发生由全反式向顺式的异构化，大大降低了其生物活性，而且最终类胡萝卜素溶液的色系都会发生变化；三是将类胡萝卜素晶体与植物油混合后研磨，此方法的优点在于工艺中没有用到有机溶剂，不存在安全性方面的担忧，而且类胡萝卜素分子没有经受高温过程，全反式含量高，但此方面的一个明显的缺点就是常规方法不易将类胡萝卜素晶体研磨到足够的细度，导致最终产品 的生物利用度不高。
US20100267838,US20120039970,US20070173547等申请中都利用有机溶剂溶解类胡萝卜素后得油相，与水相混合乳化后，脱除或不脱除有机溶剂得到类胡萝卜素微胶囊制剂的方法。
US20110207831中介绍了通过熔融法制备类胡萝卜素微胶囊制剂，由于部分类胡萝卜素在高温过程中发生了降解和异构化，导致最终产品的颜色偏黄，生物活性降低。
US20080220071中揭示了一种包括类胡萝卜素水溶性悬浮液，其中除了使用溶剂法外，还用到研磨机研磨方式制备油相，但在此申请中，为了达到所需细度，油相要经多次长时间的循环，这对生产过程中的能耗和类胡萝卜素分子的稳定都是不利的。
US20100120922中公开了一种利用研磨法生产类胡萝卜素水溶性微胶囊溶液的方法，在此过程中，为了将类胡萝卜素研磨到相应的细度，不得不在配方中加入大量的醇类溶剂如甘油、丙二醇等以降低油相研磨时的粘度，这对最终产品中有效成分含量的提高，及其稳定性是不利的。
CN109156827中提到一种红色系胡萝卜素制剂的制备方法，利用纳米研磨机研磨类胡萝卜素胶体溶液，在此过程中为了使类胡萝卜素晶体达到纳米分散，一方面要循环研磨，研磨时间很长，压力很高，另一方面要尽量减少研磨时溶液的粘度，这就要求在研磨前加入大量的水(往往控制研磨时固含量小于10％)，这对后续的喷雾干燥造粒过程是不利的。
US20080207775中描述一种水溶性类胡萝卜素微胶囊溶液的制备，将部分水相与类胡萝卜晶体混合后应用研磨机研磨，再在反应釜搅拌情况下补加部分包埋性壁材、填充剂、抗氧化剂等形成二次包埋。在此过程中，由于只经过一次研磨，终产品中类胡萝卜素粒径较粗，达0.6m，这对其在人体中生物利用度的提高还是不够的。
总之，在先前通过研磨法生产类胡萝卜素微胶囊制剂时，一个关键点就是如何有效地降低产品的粒径，以提高其生物利用度，特别是如果研磨时溶液的粘度较大，产品的粒径就更难减下来。为降低粒径，一个方法是通过长时间多次循环研磨，这不仅会大大增加生产时能耗，而且对类胡萝卜素稳定性有不好的影响；另一个方法，就是在配方中加入大量的水或水溶性溶剂如异丙醇、丙二醇以降低研磨时的粘度，这种方法效果不是很明显，而且对后续的喷雾干燥过程是不利的。有必要找到一种能有效减小研磨后产品粒径，提高其生物利用度和稳定性的类胡萝卜素水分散性微胶囊制剂的方法。
发明内容
本发明提供了一种高生物利用度高稳定性类的胡萝卜素水分散型微胶囊制剂的制备方法，所述制备方法包括如下步骤：a)将水溶性胶体和填充物质的一部分溶解于水中，以形成水相；b)将类胡萝卜素晶体加入到所述水相中搅拌后分散，以形成分散液；c)将所述分散液进入第一级研磨机中进行第一次研磨，形成一级研磨液；d)向所述一级研磨液中补加到剩余的水溶性胶体和填充物质中，再进入第二级研磨机中进行 第二次研磨，以得到二级研磨液；e)将所述二级研磨液中水份干燥后，以得到类胡萝卜素干粉或微粒。其中，根据需要，可以将研磨完成的纳米级类胡萝卜素分散液中水份干燥后得类胡萝卜素微胶囊干粉/微粒，常规的干燥方法包括喷雾干燥法、喷雾冷凝-淀粉床流化干燥法等。
在本发明的制备方法的优选技术方案中，优选地，所述类胡萝卜素为β-胡萝卜素、叶黄素、番茄红素、斑蝥黄素、玉米黄素或虾青素；所述水溶性胶体为变性淀粉、明胶、酪蛋白、阿拉伯胶、大豆分离蛋白中的一种或几种；所述填充物质为蔗糖、麦芽糊精、糖浆中的一种或几种。
在本发明的制备方法的优选技术方案中，优选地，所述第一级研磨机和所述第二级研磨机中粉磨介质为食品级卫生材料，包括306L型不锈钢、碳化钨、氧化锆、钇稳定的氧化锆珠。更优选地，所述第一级研磨机中粉磨介质的珠粒粒径在0.6-0.8mm之间；所述第二级研磨机中粉磨介质的珠粒粒径在0.3-0.4mm之间。
在本发明的制备方法的优选技术方案中，优选地，步骤a)中所述水溶性胶体的加入量为总水溶性胶体量的5-95wt.％，所述填充物质的加入量为总填充物质量的5-95wt.％。
在本发明的制备方法的优选技术方案中，优选地，步骤b)中所述分散液的固含量在5-50wt.％之间。
在本发明的制备方法的优选技术方案中，优选地，步骤c)中进行第一次研磨直至所述类胡萝卜素晶体颗粒粒径为0.5-1.5μm，停止研磨，以得到一级研磨液。
在本发明的制备方法的优选技术方案中，优选地，步骤d)中第二次加入水溶性胶体的加入量为总水溶性胶体量的95-5wt.％。
在本发明的制备方法的优选技术方案中，优选地，步骤d)中第二次填充物质的加入量为配方中总填充物质量的95％-5wt.％。
在本发明的制备方法的优选技术方案中，优选地，步骤d)中进行第二次研磨直至所述类胡萝卜素晶体颗粒粒径为150-600nm，停止研磨，以得到二级研磨液。
在本发明的制备方法的优选技术方案中，优选地，在进行第一次研磨前，加抗氧化剂，所述抗氧化剂为合成生育酚、天然维生素E、抗坏血酸、抗坏血酸棕榈酸酯中一种或几种。更优选地，所述抗氧化剂的加入量为终产品质量的1.25％-5.0wt.％。
在本发明的制备方法的优选技术方案中，优选地，在本发明的制备方法的优选技术方案中，优选地，所述类胡萝卜素水分散型微胶囊制剂中类胡萝卜素含量在1.0-30wt.％之间。
总之，本发明的制备方法是将部分水溶性胶体、填充物质溶解于水中形成水相，将类胡萝卜素晶体分散于水相中通过一级研磨后，再补加剩余的水溶性胶体和填充物质，经过第二级研磨，得到类胡萝卜素纳米分散的水溶性悬浮液，根据需要，可以将此水溶性悬浮液经喷雾干燥或喷雾冷凝工艺得到类胡萝卜素微胶囊干粉或微粒。
工艺中应用两级研磨机进行研磨能在较短时间内有效地完成类胡萝卜素的纳米级分散，两级研磨机中粉磨介质滚珠粒径不同，第一级研磨机中粉磨介质滚珠粒径粗(滚珠粒径在0.6-0.8mm之间)，达到初 磨效果，经过第一级研磨后，颗粒粒径达1μm左右；第二级研磨机中粉磨介质滚珠粒径细(滚珠粒径在0.3-0.4mm之间)，进行精磨，最终达到纳米级分散，颗粒粒径一般为500nm以下，更优选为200-300nm。两级球磨配合应用，能在使终产品中类胡萝卜素在较短时间内达到纳米分散的效果，研磨时间大大减少，由常规单级循环研磨6小时以上，缩短为0.5-2.0小时。
包被性的水溶性胶体、填充物质等水相中物质之所以要在两次研磨前分别加入，是考虑到研磨效果与研磨时溶液的粘度息息相关，粘度越小，越有利于研磨，反之，粘度越大，研磨时颗粒越不易粉碎，所需时间就会越长，能耗越高。也就是说，在第一次研磨前水相制备时，只加入部分水溶性胶体和填充物质，与类胡萝卜素晶体混合分散，由于其中固形物含量相对较低，研磨时溶液粘度较小，进行研磨时，比较容易达到粗磨效果(颗粒粒径为1μm左右)，后进入第二级研磨，在进入第二级研磨前再补加余下的水溶性胶体和填充物质，由于此时溶液中颗粒粒径已经较小，达到了微米级，此时补充固体物质对研磨溶液的粘度影响不是很大，而且在溶液中颗粒已经较小的情况下，粘度对研磨效果影响不大，能比较容易在较短时间内使颗粒粒径进一步达到纳米级分散的效果。
当然针对不同的类胡萝卜素晶体，以及同一类胡萝卜素晶体，但不同的浓度情况下，研磨时要求的固形物含量(或粘度)要求是不一样的。当终产品中类胡萝卜素浓度低时(类胡萝卜素晶体的投入量较小)，一次研磨时固形物浓度可以高些，反之，当类胡萝卜素晶体的投 入量较大时，为了达到理想的研磨效果，研磨液中固形物含量要求低些。比如，经过多次摸索，发现当终产品中类胡萝卜素含量在1％左右，一次研磨时可以投入水溶性胶体和填充物质总的量的95％，固形物含量可达50％。而当终产品中类胡萝卜素含量达30％时，一次研磨时固形物含量只能在5％左右，在此较低的固形物含量情况下，才能保证一次研磨时较低的粘度，从而达到较好的研磨效果。
水溶性胶体分批加入还有一个意想不到的效果，那就是能使终产品中类胡萝卜素形成二次包埋，大大增强终产品中类胡萝卜素的含量稳定性。主要是因为在第一次水溶性胶体与类胡萝卜素晶体一起研磨时，类胡萝卜素晶体在粉磨介质滚珠作用下不断形成微粉，分散于水溶性胶体溶液中从而形成微米级液滴，此为第一次包埋。在第二次研磨前再补加水溶性胶体，微米级分散液滴在研磨作用于不断破碎、重新组合等，形成新的纳米级液滴，在此过程中，补加的水溶性胶体重新在这些纳米级液滴表面包裹，形成第二次包埋。二次包埋对终产品的稳定性、耐压性都有很好的正面影响。
所述的研磨机为市场上可以采购到的球磨机、砂磨机等，主要结构为有一个水平放置、绕水平轴旋转的中空筒体，筒体内装有粉磨介质和被磨物料，当筒体旋转时介质和物料被提升，到一定高度后受重力作用下落，粉磨介质的运动使物料受到挤压、摩擦、冲击、磨剥、剪切等作用而粉碎。申请工艺用到的研磨机中粉磨介质为食品级卫生材料，包括306L型不锈钢，或碳化钨，或氧化锆等，优选钇稳定的氧化锆珠。
水溶性胶体为市场上可以采购到的，具有乳化稳定作用的常规胶体类物质，包括变性淀粉、明胶、酪蛋白、阿拉伯胶、大豆分离蛋白等中的一种或几种。
填充物质包括蔗糖、麦芽糊精、糖浆等中的一种或几种。
在第一次研磨前为了减少研磨时溶液中固含量，降低粘度，只需将部分水溶性胶体和填充物质加入到水相中。第一次加入的水溶性胶体和填充物质分别占配方中总水溶性胶体和填充物质的5％-95％。
第一次研磨前固含量在5-50％之间。
第一次研磨时研磨机中粉磨介质滚珠粒径在0.6-0.8mm之间。
将第一次研磨得到的微米级分散液取出后，加入余下的水溶性胶体和填充物质，余下的水溶性胶体和填充物质分别占配方中总水溶性胶体和填充物质量的95％-5％，进入第二级研磨机研磨。
第二次研磨时研磨机中粉磨介质滚珠粒径在0.3-0.4mm之间。
根据需要，配方中可以加入一定量的抗氧化剂，如合成生育酚、天然维生素E、抗坏血酸、抗坏血酸棕榈酸酯、BHT等。
经过此“二次研磨，二次包埋”工艺得到的类胡萝卜素制剂生产过程中操作方便，研磨时间短，能耗低，最终产品中液滴达纳米级分散，且分散均匀，粒径跨度小，而且由于类胡萝卜素分子得到两次包埋，所以稳定性好，易于压片成型。相较于先前工艺，此工艺具有显著优点。
具体实施方式
通过以下实施例来对本发明作进一步具体说明，但不仅限于以下实施例和实施例中的工艺参数范围。
实施例1
取变性淀粉(PG 2000，购自Ingredion)475g，蔗糖25g，完全溶解于580ml 50℃的热水中形成水溶性胶体溶液。取beta-胡萝卜素晶体15g，合成生育酚65g，加入到上述胶体溶液中(固含量50％)，在砂磨机(Sunller Machine)进行第一次研磨，粉磨介质钇稳定氧化锆珠粒径在0.6-0.8mm之间，研磨0.3hr后取样检测，beta-胡萝卜素颗粒粒径为1.5μm，停止研磨，得一级研磨液。
称取变性淀粉(PG 2000，Ingredion)25g，蔗糖475g于上述一级研磨液中，搅拌分散后，进入第二台砂磨机(Sunller Machine)进行第二次研磨，粉磨介质钇稳定氧化锆珠粒径在0.3-0.4mm之间，研磨0.2hr后取样检测，beta-胡萝卜素颗粒粒径为250nm，停止研磨，得二级研磨液。此研磨液水分散性很好，水中分散后呈透明红色，其中beta-胡萝卜素含量为1.05％。
实施例2
取阿拉伯胶40g，麦芽糊精545g，完全溶解于3080ml 75℃的热水中形成水溶性胶体溶液，降温至45℃。取叶黄素晶体125g(其中叶黄素晶体115g，含量80.7％，玉米黄素10g，含量83.4％)，天然维生素E 40g，加入到上述胶体溶液中(固含量19.6％)，在砂磨机(Sunller Machine)进行第一次研磨，粉磨介质钇稳定氧化锆珠粒径在0.6-0.8mm之间，研磨1.0hr后取样检测，叶黄素颗粒粒径为0.9μm，停止研磨， 得到一级研磨液。
称取阿拉伯胶760g，糖浆30g于上述一级研磨液中，搅拌分散后，进入第二台砂磨机(Sunller Machine)进行第二次研磨，粉磨介质钇稳定氧化锆珠粒径在0.3-0.4mm之间，研磨1.0hr后取样检测，叶黄素颗粒粒径为150nm，停止研磨，得二级研磨液。此研磨液水分散性很好，水中分散后呈透明黄色。
将二级研磨液通过喷雾干燥方法去除其中水份，得叶黄素微胶囊干粉，其中叶黄素含量为6.43％，此叶黄素干粉的贮存稳定性很好，其稳定性保留率数据见表2。
实施例3
取明胶200g，蔗糖250g，完全溶解于2575ml 70℃的热水中形成水溶性胶体溶液，降温至40℃。取斑蝥黄素晶体185g(含量97.3％)，抗坏血酸棕榈酸酯45g，加入到上述胶体溶液中(固含量20.9％)，在砂磨机(Sunller Machine)进行第一次研磨，粉磨介质钇稳定氧化锆珠粒径在0.6-0.8mm之间，研磨0.5hr后取样检测，斑蝥黄素颗粒粒径为1.5μm，停止研磨，得一级研磨液。
称取明胶250g，麦芽糊精275g，抗坏血酸30g于上述一级研磨液中，搅拌分散后，进入第二台砂磨机(Sunller Machine)进行第二次研磨，粉磨介质钇稳定氧化锆珠粒径在0.3-0.4mm之间，研磨0.5hr后取样检测，斑蝥黄素颗粒粒径为276nm，停止研磨，得二级研磨液。此研磨液水分散性很好，水中分散后呈透明红色。
将二级研磨液通过喷雾-淀粉流瞬时成型方法去除其中水份，得斑 蝥黄素微胶囊微粒，其中斑蝥黄素含量为11.56％，此斑蝥黄素微粒的贮存稳定性很好，其稳定性保留率数据见表2。
实施例4
取大豆分离蛋白120g，酪蛋白30g，糖浆40g，麦芽糊精30g，完全溶解于10340ml 80℃的热水中形成水溶性胶体溶液，降温至40℃。取番茄红素晶体300g(含量96.2％)，合成生育酚12g，天然维生素E 12g，加入到上述胶体溶液中(固含量4.99％)，在砂磨机(Sunller Machine)进行第一次研磨，粉磨介质碳化钨，珠粒粒径在0.6-0.8mm之间，研磨1.5hr后取样检测，番茄红素颗粒粒径为0.5μm，停止研磨，得一级研磨液。
称取大豆分离蛋白180g，酪蛋白90g，糖浆90g，麦芽糊精50g于上述一级研磨液中，搅拌分散后，进入第二台砂磨机(Sunller Machine)进行第二次研磨，粉磨介质306不锈钢，珠粒粒径在0.3-0.4mm之间，研磨0.5hr后取样检测，番茄红素颗粒粒径为600nm，停止研磨，得二级研磨液。此研磨液水分散性很好，水中分散后呈透明红色。
将二级研磨液通过喷雾-淀粉流瞬时成型方法去除其中水份，得番茄红素微胶囊微粒，其中番茄红素含量为29.69％，此斑蝥黄素微粒的贮存稳定性很好，其稳定性保留率数据见表2.
比较实施例5
取明胶450g，蔗糖525g，完全溶解于1000ml 70℃的热水中形成水溶性胶体溶液，降温至40℃。取斑蝥黄素晶体185g(含量97.3％)，抗坏血酸棕榈酸酯45g，抗坏血酸30g，加入到上述胶体溶液中(固含 量55.3％)，在砂磨机(Sunller Machine)进行研磨，粉磨介质钇稳定氧化锆珠粒粒径在0.3-0.4mm之间，研磨1.0hr后每隔2.0小时取样检测，斑蝥黄素颗粒粒径，当颗粒粒径达500nm以下时停止研磨，得研磨液。表1中显示了不同取样点斑蝥黄素颗粒粒径变化情况。
表1不同时间点取样得到的水分散液中斑蝥黄素颗粒粒径
研磨时间(hr) 颗粒粒径(nm)
1.0 2548
3.0 976
5.0 635
6.0 488
此研磨液水分散性很好，水中分散后偏粉红色，不透明。将研磨液通过喷雾-淀粉流瞬时成型方法去除其中水份，得斑蝥黄素微胶囊微粒，其中斑蝥黄素含量为11.24％，此斑蝥黄素微粒的贮存稳定性保留率数据见表2。
比较实施例6
取阿拉伯胶800g，麦芽糊精575g，完全溶解于3080ml 75℃的热水中形成水溶性胶体溶液，降温至45℃。取虾青素晶体125g(含量80.7％)，天然维生素E 40g，加入到上述胶体溶液中(固含量33.3％)，在砂磨机(Sunller Machine)进行第一次研磨，粉磨介质钇稳定氧化锆珠粒径在0.6-0.8mm之间，研磨1.5hr后取样检测，虾青素颗粒粒径为1.2μm，停止研磨，得一级研磨液。
将上述一级研磨液直接进入第二台砂磨机(Sunller Machine)进行 第二次研磨，粉磨介质钇稳定氧化锆珠粒径在0.3-0.4mm之间，研磨1.0hr后取样检测，虾青素颗粒粒径为478nm，停止研磨，得二级研磨液。
将二级研磨液通过喷雾干燥方法去除其中水份，得虾青素微胶囊干粉，其中虾青素含量为6.35％，其稳定性保留率数据见表2.
表2各实施例样品中类胡萝卜素含量保留率
(实验条件：40℃，敞口见光)
Figure PCTCN2020078522-appb-000001
从以上实施例和比较实施例中可以看出，相对于二级研磨，包被性壁材和填充物质一次性加入，大大增加了研磨液中固形物含量，从而加大了其粘度，经过长达6.0小时的研磨，才将研磨液中的类胡萝卜素颗粒粒径降至500nm以下，而本发明中的二次研磨，只需2.0小时就可以将粒径降到200nm左右。而且将包被性壁材分批加入，不仅降低了研磨时的粘度，提高研磨效率，而且能起到二次包埋效果，大大提高了终产品制剂中类胡萝卜素的稳定性，6个月加速稳定性试验中，其含量保留率在为提升。
本发明通过上面的实施例进行举例说明，但是，应当理解，本发明并不限于这里所描述的特殊实施例和实施方案。在这里包含这些特殊实施例和实施方案的目的在于帮助本领域中的技术人员实践本发明。任何本领域中的技术人员很容易在不脱离本发明精神和范围的情况下进行进一步改进和完善，因此本发明只受到本发明权利要求的内容和范围的限制，其意图涵盖所有包括在由附录权利要求所限定的本发明精神和范围内的备选方案和等同方案。

Claims (12)

  1. 一种高生物利用度高稳定性类的胡萝卜素水分散型微胶囊制剂的制备方法，所述制备方法包括如下步骤：
    a)将水溶性胶体和填充物质的一部分溶解于水中，以形成水相；
    b)将类胡萝卜素晶体加入到所述水相中搅拌后分散，以形成分散液；
    c)将所述分散液进入第一级研磨机中进行第一次研磨，以形成一级研磨液；
    d)向所述一级研磨液中补加到剩余的水溶性胶体和填充物质中，再进入第二级研磨机中进行第二次研磨，以得到二级研磨液；
    e)将所述二级研磨液中水份干燥后，以得到类胡萝卜素干粉或微粒。
  2. 如权利要求1所述的制备方法，其中，所述类胡萝卜素为β-胡萝卜素、叶黄素、番茄红素、斑蝥黄素、玉米黄素或虾青素；所述水溶性胶体为变性淀粉、明胶、酪蛋白、阿拉伯胶、大豆分离蛋白中的一种或几种；所述填充物质为蔗糖、麦芽糊精、糖浆中的一种或几种。
  3. 如权利要求1所述的制备方法，其中，所述第一级研磨机和所述第二级研磨机中粉磨介质为食品级卫生材料，包括306L型不锈钢、碳化钨、氧化锆、钇稳定的氧化锆珠。
  4. 如权利要求2所述的制备方法，其中，所述第一级研磨机中粉磨介质的珠粒粒径在0.6-0.8mm之间；所述第二级研磨机中粉磨介质 的珠粒粒径在0.3-0.4mm之间。
  5. 如权利要求1所述的制备方法，其中，步骤a)中所述水溶性胶体的加入量为总水溶性胶体量的5-95wt.％，所述填充物质的加入量为总填充物质量的5-95wt.％。
  6. 如权利要求1所述的制备方法，其中，步骤b)中所述分散液的固含量在5-50wt.％之间。
  7. 如权利要求1所述的制备方法，其中，步骤c)中进行第一次研磨直至所述类胡萝卜素晶体颗粒粒径为0.5-1.5μm，停止研磨，以得到一级研磨液。
  8. 如权利要求1所述的制备方法，其中，步骤d)中第二次加入水溶性胶体的加入量为总水溶性胶体量的95-5wt.％，第二次填充物质的加入量为配方中总填充物质量的95％-5wt.％。
  9. 如权利要求1所述的制备方法，其中，步骤d)中进行第二次研磨直至所述类胡萝卜素晶体颗粒粒径为150-600nm，停止研磨，以得到二级研磨液。
  10. 如权利要求1-9任一的所述的制备方法，其中，在进行第一次研磨前，还添加抗氧化剂，所述抗氧化剂为合成生育酚、天然维生素E、抗坏血酸、抗坏血酸棕榈酸酯中一种或几种。
  11. 如权利要求10所述的制备方法中，所述抗氧化剂的加入量为终产品质量的1.25％-5.0wt.％。
  12. 如权利要求1所述的制备方法，其中，所述类胡萝卜素水分散型微胶囊制剂中类胡萝卜素含量在1.0-30wt.％之间。
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CN113575948B (zh) * 2021-08-04 2024-01-26 上海健康医学院 一种番茄红素软胶囊及其制备方法和应用
CN113785987A (zh) * 2021-09-14 2021-12-14 万华化学集团股份有限公司 一种维生素a微胶囊的制备方法
CN115119904B (zh) * 2022-05-23 2024-02-27 万华化学(四川)有限公司 一种高全反式类胡萝卜素微胶囊的制备方法及微胶囊
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