WO2015003536A1 - 油分散性类胡萝卜素制剂的制备方法 - Google Patents

油分散性类胡萝卜素制剂的制备方法 Download PDF

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WO2015003536A1
WO2015003536A1 PCT/CN2014/079069 CN2014079069W WO2015003536A1 WO 2015003536 A1 WO2015003536 A1 WO 2015003536A1 CN 2014079069 W CN2014079069 W CN 2014079069W WO 2015003536 A1 WO2015003536 A1 WO 2015003536A1
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oil
carotenoid
preparation
dispersible
astaxanthin
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PCT/CN2014/079069
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English (en)
French (fr)
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仇丹
石立芳
李建东
陈志荣
周佳超
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浙江新维普添加剂有限公司
浙江大学
浙江新和成股份有限公司
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Priority to AU2014289828A priority Critical patent/AU2014289828B2/en
Priority to CA2919468A priority patent/CA2919468C/en
Priority to JP2016524662A priority patent/JP6141529B2/ja
Priority to EP14823839.7A priority patent/EP3020396B1/en
Priority to US14/902,553 priority patent/US10212957B2/en
Publication of WO2015003536A1 publication Critical patent/WO2015003536A1/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
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • 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
    • 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
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • A61K31/01—Hydrocarbons
    • 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
    • A61K31/045—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
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/31—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/345—Alcohols containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35—Ketones, e.g. benzophenone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/10—General cosmetic use

Definitions

  • the invention relates to a preparation method of a carotenoid preparation, in particular to a preparation method of an oil-dispersible carotenoid preparation.
  • Carotenoids are widely found in nature. Currently, commercial carotenoid products mainly have ⁇ - Carotene, astaxanthin, lycopene, canthaxanthin, lutein, etc., these substances are widely used in the fields of food, cosmetics, feed and pharmaceutical industries as nutritional fortifiers and colorants. Carotenoids are insoluble in water, have low solubility in oil, and are very sensitive to light, heat and oxygen. They cannot be directly applied. Generally, carotenoids need to be ultra-fine and made into different preparation forms. Medicine, health products, food, feed and many other fields. Carotenoids can significantly improve bioavailability, increase coloration and reduce dosage after formulation.
  • WO91/06292 and WO94/19411 describe the grinding of ⁇ -carotene to 2 to 10 ⁇ m using a colloid mill. The particles are then dried to form a water-dispersible carotenoid powder.
  • US3998753 describes a process for the preparation of water-dispersible carotenoids in which the carotenoid has a particle size of less than 1 ⁇ m. .
  • the method firstly prepares a carotenoid and other additives into a solution of an organic solvent, and then adds it to an aqueous solution containing gelatin, a dispersing agent and a stabilizer, and forms a solution by high-speed shearing; removing the organic solvent and spray-drying to obtain a desired product.
  • the method for preparing water-dispersible carotenoid powder described in EP0065193 is to carotenoid at 50 to 200 ° C. Dissolved in a volatile water-miscible solvent in 10 seconds, then rapidly mixed with a protective colloid-containing aqueous solution at 0 to 50 °C. Carotenoids are less than 0.5 ⁇ m. The size is dispersed in the protective colloid, the solvent is removed and dried to obtain a carotenoid powder; CN102361561A A ready-to-use stable suspension of partially amorphous carotenoid particles is prepared by a similar process.
  • CN102281859A Disclosed is a method for preparing an emulsion composition, which is mainly obtained by mixing a fat phase of a carotenoid previously dissolved with an aqueous phase containing a plurality of emulsifiers; CN101312655B A similar process was also employed and the emulsion was spray dried to give the product.
  • CN1233169A reports two supercritical fluid treatment processes: A The process first dissolves carotenoids in supercritical dimethyl ether under high temperature and high pressure, and then rapidly decompresses to obtain powdery carotenoid granules; The process first dissolves the carotenoid in a subcritical or supercritical compressed gas under high temperature and high pressure, and then disperses the solution in other ingredients, and then removes the compressed gas in the mixture to prepare a powdery preparation.
  • US6056791 also reports a process for mixing carotenoids with supercritical fluids under pressure to form 5%-90% A solution of supercritical fluid.
  • the melting point of the selected supercritical fluid is at least 40 ° C lower than the melting point of the carotenoid. Then adjust the temperature to 50 °C higher or lower than the melting point of the supercritical fluid And reduce the pressure to atmospheric pressure. Under these conditions, the supercritical fluid is rapidly vaporized, and the carotenoid particles can have a particle size of 0.7 ⁇ m to 5 ⁇ m.
  • ⁇ -carotene is rapidly decompressed after being dissolved in a supercritical fluid to obtain fine particles ⁇ - Carotene, and then add other ingredients to make a solid agent.
  • Patent Publication No. CN1836652A the preparation method of a water-dispersible carotenoid powder applied in 2005
  • Preparation method of a high all-trans ⁇ -carotene preparation applied in 2007 Patent Publication No. CN101016259A
  • 2009 Method for preparing nano-dispersed high-trans-type carotenoid microcapsules Application No. CN101549273B
  • 2010 A method for preparing carotenoid microcapsules with controllable isomer ratios (Patent Publication No. CN101879428A).
  • CN102341002A Using a modified heating process to treat a carotenoid oil suspension to obtain 0.01 to 10 g / kg
  • the carotenoid vegetable oil solution but the concentration is only 1%, and the carotenoid has poor chemical stability in the oil solution, and is prone to side reactions.
  • CN1185433 A liquid and oil-mixable carotenoid preparation is reported, which is mainly prepared by adding a carotenoid aqueous dispersion phase to an oil phase.
  • W/O emulsion in which the droplet size of the aqueous phase is close to 1 ⁇ m, the carotenoid particle size is 0.1 to 0.2 ⁇ m, but the carotenoid content can only be reached due to the large amount of solvent, emulsifier and auxiliary materials.
  • About 1%, and the complex emulsion system is less stable when applied, and it is difficult to adapt to harsh processing conditions such as high temperature and high pressure.
  • the carotenoids are ground together with soybean phospholipids into a latex solution, and then diluted with vegetable oil to be pulverized to obtain a microparticle emulsion, but the carotenoid has a particle size of only 5 to 10 ⁇ m;
  • the current common carotenoid oil suspension dosage form is obtained by directly mixing carotenoid crystals with vegetable oil.
  • CN101828693A A carotenoid oil suspension having a particle size of about 10 ⁇ m is obtained by treating carotenoid crystals with tetrahydrofuran, ethanol, vegetable oil or the like;
  • CN102552173A A carotenoid oil suspension having an average particle diameter of less than 5 ⁇ m is obtained by a process of atomizing a carotenoid solution into a vegetable oil; The uniformity of the process and the particle size of the carotenoids could not reach the level of the emulsion.
  • the water-dispersible dosage form of carotenoids generally achieves a smaller particle size and is very stable after being made into microcapsules; while the oil-dispersible dosage form has a relatively large particle size and the active substance is directly exposed to the dispersion.
  • the stability is poor, and a few of them can achieve a smaller particle size, but can only be reached due to the formulation limitation.
  • the upper limit of the content of about 1%, and the carotenoid in the preparation has no dense protective layer.
  • the invention provides a preparation method of an oil-dispersible carotenoid preparation, which not only contains carotenoids as high as 2% to 14%
  • the carotenoid particles have an average particle diameter of 0.1 to 1 ⁇ m, and the carotenoid particles have a dense water-soluble colloidal protective layer on the surface.
  • a method for preparing an oil-dispersible carotenoid preparation, in parts by weight, comprising the steps of:
  • carotenoid microcapsules 100 parts with 100 to 400 parts of vegetable oil, 0.1 to 1 part of antioxidant B Mixing, grinding in a colloid mill for 1 to 5 times in a nitrogen atmosphere at 10 to 30 ° C to obtain a uniform oil-dispersible carotenoid preparation, wherein the carotenoid particles have an average particle diameter of 0.1 to 1 ⁇ m. ;
  • carotenoid microcapsules contain 10.5 to 35.8 carotenoids, 0.1 to 1 Part of the antioxidant A, the rest is a water-soluble colloid; the preparation process of the carotenoid microcapsules refers to the method described in CN1836652A or CN101549273B.
  • the antioxidant A is vitamin C, vitamin C sodium salt, isovitamin C or isovitamin C sodium salt;
  • the antioxidant B is tocopherol, ethoxyquin, 2,6-di-tert-butyl-4-methylphenol (BHT) Or tert-butyl hydroquinone (TBHQ);
  • the carotenoid is ⁇ -carotene, astaxanthin, lycopene, canthaxanthin or lutein;
  • the water-soluble colloid is gelatin, starch octenyl succinate or gum arabic;
  • the vegetable oil is soybean oil, corn oil, sunflower oil, peanut oil or salad oil.
  • the carotenoid content of the oil-dispersible carotenoid preparation is determined by ultraviolet spectroscopy; the carotenoid particle size is determined by a laser particle size analyzer, and the specific method: A microporous membrane having a pore size of 0.3 ⁇ m is used to filter oil-dispersible carotenoid preparations, collect fine particles in oil, and then add water to disperse the particles, and take an aqueous phase sample for laser particle size analyzer.
  • An advantage of the present invention is an oil-dispersible carotenoid preparation
  • the carotenoid particles have a dense water-soluble colloid layer on the surface and are highly stable, and can produce carotenoids with a content of 2% to 14% and an average particle size of only 0.1 to 1 ⁇ m. Oil-dispersible carotenoid preparation, practical.
  • Figure 1 is an optical micrograph of an oil-dispersed astaxanthin preparation prepared in Example 1, with a magnification of 200 times.
  • Figure 2 is an optical micrograph of an oil-dispersed astaxanthin preparation prepared in a comparative example at a magnification of 200 times.
  • Figure 3 is an oil-dispersed astaxanthin preparation prepared in Example 1 and an oil-dispersed astaxanthin preparation prepared in the comparative example. Comparison of thermal stability.
  • the aqueous solution was mixed, stirred and beaten, and then homogenized in a high-pressure homogenizer for 5 hours.
  • the emulsion was first vacuum-dissolved, and then spray-dried to obtain 100 g of astaxanthin microcapsules containing astaxanthin 10.5 g.
  • astaxanthin microcapsules 100 g were mixed with 100 g of soybean oil containing 0.2 g of tocopherol in a nitrogen atmosphere and 30 It was ground 3 times in a colloid mill at °C to obtain a uniform oil-dispersed astaxanthin preparation containing 5.0% astaxanthin and an average diameter of astaxanthin of 0.82 ⁇ m.
  • FIG. 1 is the embodiment 1
  • a micrograph of the prepared oil-dispersed astaxanthin preparation showed that the astaxanthin was coated with a significant embedding material, and the average particle size of the dispersed particles in the oil was 30.34 ⁇ m.
  • the sample was filtered and dispersed with water.
  • the average particle size of astaxanthin in the aqueous phase was 0.82 ⁇ m.
  • Figure 2 is a micrograph of the oil-dispersed astaxanthin preparation prepared in the comparative example. The astaxanthin was present in the form of crystals. Trail is 1.21 ⁇ m.
  • the oil-dispersed astaxanthin preparation prepared in Example 1 and the oil-dispersed astaxanthin preparation prepared in the comparative example were separately placed in 90
  • the accelerated decomposition test was carried out at ° C, and the difference in stability was compared by measuring the content of astaxanthin in samples at different times.
  • the abscissa is time and the ordinate is the astaxanthin content in the sample determined by ultraviolet spectroscopy
  • a The curve represents the oil-dispersed astaxanthin preparation prepared in Example 1
  • the B curve represents the oil-dispersed astaxanthin preparation prepared in the comparative example.
  • the oil-dispersed astaxanthin preparation prepared in the comparative example was heated 8 Significant degradation began after an hour, and the astaxanthin content did not decrease significantly after 72 hours of the oil-dispersed astaxanthin preparation prepared in Example 1, indicating Example 1
  • the prepared oil-dispersed astaxanthin preparation has a markedly improved thermal stability.
  • the above ⁇ -carotene suspension was pumped into a 4L volume with a slurry at a flow rate of 8 kg / hour, having 4
  • the bottom of the four-stage dissolution vessel with a height-to-diameter ratio of 4 was stirred at the same time.
  • the dichloromethane was preheated to 37 °C through a coil preheater at a flow rate of 200 kg / hour, and then sent to the bottom of the dissolution tank to control the temperature inside the reactor.
  • the pressure is 0.25Mpa
  • the sample time is about 15 minutes.
  • the above ⁇ -carotene isopropanol dispersion was pumped at 7 kg/ The hourly flow was passed to another supergravity rotary packed bed beaker, and the prepared octenyl succinate solution was fed into the supergravity rotary packed bed beater at a flow rate of 27 kg/hour. Traffic is about 35 kg / hour of the beating liquid; the above-mentioned beating liquid was directly spray-dried to obtain 100 kg of ⁇ -carotene microcapsules containing 35.8 kg of ⁇ -carotene.
  • the microporous membrane is filtered, and the filter cake is washed with ethanol and dried to obtain an ultra-fine canthaxanthin powder cake; the above-mentioned canthaxanthin powder cake and 1 L containing 0.5 g of isovitamin C and 76.1 g of gum arabic
  • the aqueous solution was mixed, stirred and beaten, and then homogenized in a high-pressure homogenizer for 4 hours.
  • the emulsion was first vacuum-dissolved and then spray-dried to obtain 100 g of canthaxanthin microcapsules containing 23.4 g of canthaxanthin.
  • canthaxanthin microcapsules 100 g were mixed with 300 g of sunflower oil containing 0.4 g of BHT in a nitrogen atmosphere and 20 The mixture was ground 3 times in a colloid mill at ° C to obtain a uniform oil-dispersed canthaxanthin preparation containing 5.62% of canthaxanthin, and the average particle size of canthaxanthin was 0.83 ⁇ m.
  • the lycopene suspension was pumped into a 4 L volume at a flow rate of 7 kg/hour, and the height-to-diameter ratio with 4 layers of stirring was 4
  • the dichloromethane was preheated to 37 °C through a coil preheater at a flow rate of 180 kg/hour, and then sent to the bottom of the dissolution vessel to control the temperature in the kettle to be 38 ° C and the pressure was 0.27 MPa.
  • the sample is analyzed and it is known that the solution has been dissolved into a lycopene solution; the above lycopene solution and isopropanol (1000 kg/ The flow rate of the hour is simultaneously introduced into the supergravity rotary packed bed crystallizer, and the control speed is 3000 rpm, and the flow rate is 1200 kg / An hourly lycopene dispersion; the above lycopene dispersion was subjected to a large portion of the solvent under reduced pressure in a falling film evaporator to obtain a lycopene isopropyl alcohol dispersion having a flow rate of 7.5 kg/hour.
  • the above lycopene isopropyl alcohol dispersion was pumped at 8 kg/ The hourly flow was passed to another supergravity rotary packed bed beaker, and the prepared octenyl succinate solution was fed into the supergravity rotary packed bed beaker at a flow rate of 26 kg/hour. Traffic is about 34 kg / hour of the beating liquid; the above beating liquid was directly spray-dried to obtain 100 kg of lycopene microcapsules containing lycopene 14.4 kg.
  • lutein crude crystals 40 g were dissolved in 2 L of chloroform to prepare a lutein solution; then the lutein solution was slowly added to the solution in the form of a spray In the kettle of 20L ethanol, the spray speed was adjusted so that the precipitated amorphous lutein particles had a particle size of less than 2 ⁇ m; after spraying, the pore size was 0.3 ⁇ m.
  • the microporous membrane is filtered, and the filter cake is washed with ethanol and dried to obtain an ultra-fine lutein powder filter cake; the above lutein powder filter cake and 1 L containing 0.3 g of isovitamin C and 83.3 g of gum arabic
  • the aqueous solution was mixed, stirred and beaten, and then homogenized in a high-pressure homogenizer for 4 hours.
  • the emulsion was first vacuum-dissolved, and then spray-dried to obtain 100 g of lutein microcapsules containing lutein 16.4 g.
  • the aqueous solution was mixed, stirred and beaten, and then homogenized in a high-pressure homogenizer for 5 hours.
  • the emulsion was first vacuum-dissolved, and then spray-dried to obtain 100 g of astaxanthin microcapsules containing astaxanthin 10.5 g.
  • astaxanthin microcapsules 100 g were mixed with 400 g of soybean oil containing 0.1 g of tocopherol in a nitrogen atmosphere and 30 It was ground once in a colloid mill at °C to obtain a uniform oil-dispersed astaxanthin preparation containing 2.1% astaxanthin and an average diameter of astaxanthin of 1.00 ⁇ m.

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Abstract

本发明公开了一种油分散性类胡萝卜素制剂的制备方法，以重量份计，包括：将 100 份类胡萝卜素微胶囊与 100 ～ 400 份植物油、 0.1 ～ 1 份油溶性抗氧化剂混合，在氮气氛和10～30℃下于胶体磨中研磨，制得均匀的油分散性类胡萝卜素制剂，其中含类胡萝卜素2%～14% ，类胡萝卜素平均粒径达到0.1～1μm ；100份类胡萝卜素微胶囊中含10.5～35.8份类胡萝卜素、0.1～1份水溶性抗氧化剂，其余为水溶性胶体。本发明的优点是油分散性剂型中类胡萝卜素颗粒表面仍有致密的水溶性胶体保护而稳定性高，并且能制备类胡萝卜素含量高达2%～14%和平均粒径仅为0.1～1μm 的油分散性类胡萝卜素制剂。

Description

油分散性类胡萝卜素制剂的制备方法
本发明涉及类胡萝卜素制剂的制备方法，特别是一种油分散性类胡萝卜素制剂的制备方法。
类胡萝卜素 (Carotenoids) 广泛存在于自然界中，目前商业化的类胡萝卜素产品主要有 β- 胡萝卜素、虾青素、番茄红素、角黄素、叶黄素等，这些物质作为营养强化剂和着色剂被普遍用于食品、化妆品、饲料和医药工业等领域。类胡萝卜素不溶于水，在油中溶解度也很小，且对光、热和氧气均十分敏感，无法直接应用，一般均需将类胡萝卜素超细化并制成不同制剂形式后方能应用于医药、保健品、食品、饲料等诸多领域。类胡萝卜素经制剂化后能显著提高生物利用度，提高着色效果并降低用量。
关于类胡萝卜素制剂的制备方法的报道，主要有以下几种方法：
WO91/06292 和 WO94/19411 介绍了使用胶体磨将 β- 胡萝卜素研磨成 2 ～ 10μm 的微粒，然后经干燥制成水分散的类胡萝卜素粉。
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径小于 1μm 。该方法先将类胡萝卜素与其它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；除去有机溶剂并喷雾干燥得到所需产品。
EP0065193 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 ℃ 在 10 秒内溶解在挥发性水可混溶的溶剂中， 然后于 0 ～ 50 ℃ 下与含保护胶体的水溶液快速混合，类胡萝卜素即以小于 0.5μm 的尺寸分散于保护胶体中，脱除溶剂并干燥得类胡萝卜素粉； CN102361561A 通过类似的工艺制备得到部分无定形类胡萝卜素颗粒的即用稳定悬浮液。
CN102281859A 披露了一种乳液组合物的制备方法，主要是将预先溶有类胡萝卜素的油脂相与含多种乳化剂的水相混合得到； CN101312655B 也采用了类似的工艺并将乳液喷雾干燥得到产品。
CN1233169A 报道了两种超临界流体处理工艺： A 工艺是先将类胡萝卜素于高温高压下溶于超临界二甲醚中，然后迅速减压得到粉末状类胡萝卜素颗粒； B 工艺是先将类胡萝卜素于高温高压下溶于亚临界或超临界的压缩气体中，然后将此溶液分散于其它配料中，再将此混合液中的压缩气体去除后制成粉末状制剂。
US6056791 也报道了一种工艺，在一定压力下，将类胡萝卜素与超临界流体混合，直到形成含 5%-90% 超临界流体的溶液。所选择的超临界流体的熔点比类胡萝卜素的熔点至少要低 40 ℃ 。然后将温度调整到比超临界流体熔点高或低 50 ℃ ，并将压力降至大气压。在此条件下超临界流体迅速气化，同时类胡萝卜素颗粒的粒径可达到 0.7μm-5μm 。
DE2943267 中提到，将 β- 胡萝卜素溶于超临界流体后迅速减压，得到细颗粒 β- 胡萝卜素，再加入其它配料制成固体药剂。
本申请人也陆续申请一系列专利，包括 2005 年申请的一种水分散性类胡萝卜素粉的制备方法（专利公开号 CN1836652A ）、 2007 年申请的一种高全反式 β- 胡萝卜素制剂的制备方法（专利公开号 CN101016259A ）、 2009 年申请的纳米分散的高全反式类胡萝卜素微胶囊的制备方法（专利公开号 CN101549273B ）和 2010 年申请的异构体比例可控的类胡萝卜素微胶囊的制备方法（专利公开号 CN101879428A ）。
以上诸多剂型均是乳液、微胶囊等水分散性或固体剂型，难以应用在油相体系中。关于应用于油相体系剂型的制备方法报道主要有：
CN102341002A 利用改变加热工艺处理类胡萝卜素油悬浮液而得到 0.01 ～ 10g /kg 的类胡萝卜素植物油溶液，但浓度最高只有 1% ，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。
CN1185433 报道了一种液体、油可混类胡萝卜素制剂，主要通过将类胡萝卜素水分散相加入油相中制成 W/O 型乳状液，其中水相液滴粒径接近 1μm ，类胡萝卜素粒径达到 0.1 ～ 0.2μm ，但由于含有大量溶剂、乳化剂和辅料使得类胡萝卜素含量最高只能达到 1% 左右，并且复杂的乳状液体系应用时稳定性较差，难以适应高温、高压等恶劣加工条件。
CN101611876 先将类胡萝卜素与大豆磷脂一起研磨成乳胶粒溶液，然后再加植物油稀释、粉碎而制得微粒乳液，但类胡萝卜素粒径只有 5 ～ 10μm ；
目前通用的类胡萝卜素油悬浮液剂型是通过直接将类胡萝卜素结晶与植物油混合研磨得到的。近年来有相关专利在此基础上做了改进， CN101828693A 通过利用四氢呋喃、乙醇、植物油等处理类胡萝卜素结晶而得到粒径约为 10μm 的类胡萝卜素油悬浮液； CN102552173A 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。
综上所述，类胡萝卜素的水分散性剂型一般能达到较小的粒径，而且制成微胶囊后稳定性很好；而油分散性剂型多数粒径较粗且有效物直接暴露于分散介质中而导致稳定性差，其中少数方法能达到较小的粒径，但因配方限制而只能达到 1% 左右的含量上限，并且制剂中类胡萝卜素都没有致密的保护层。
本发明提供了一种油分散性类胡萝卜素制剂的制备方法，不仅含类胡萝卜素高达 2% ～ 14% ，类胡萝卜素颗粒平均粒径 0.1 ～ 1μm ，而且 类 胡萝卜素颗粒表面有致密的水溶性胶体保护层。
一种油分散性类胡萝卜素制剂的制备方法，以重量份计，包括以下步骤：
将 100 份类胡萝卜素微胶囊与 100 ～ 400 份植物油、 0.1 ～ 1 份抗氧化剂 B 混合，在氮气氛和 10 ～ 30 ℃下于胶体磨中研磨 1 ～ 5 次，制得均匀的油分散性类胡萝卜素制剂，其中类胡萝卜素颗粒平均粒径为 0.1 ～ 1μm ；
所述的 100 份类胡萝卜素微胶囊中含 10.5 ～ 35.8 份类胡萝卜素、 0.1 ～ 1 份抗氧化剂 A ，其余为水溶性胶体； 类胡萝卜素微胶囊的制备工艺参照 CN1836652A 或 CN101549273B 描述的方法。
所述的抗氧化剂 A 为维生素 C 、维生素 C 钠盐、异维生素 C 或异维生素 C 钠盐；
所述的抗氧化剂 B 为生育酚、乙氧喹啉、 2,6- 二叔丁基 -4- 甲基苯酚（ BHT ）或特丁基对苯二酚（ TBHQ ）；
所述的类胡萝卜素为 β- 胡萝卜素、虾青素、番茄红素、角黄素或叶黄素；
所述的水溶性胶体为明胶、辛烯基琥珀酸淀粉酯或阿拉伯胶；
所述的植物油为大豆油、玉米油、葵花籽油、花生油或色拉油。
油分散性类胡萝卜素制剂中类胡萝卜素含量由紫外光谱测定；类胡萝卜素粒径由激光粒度仪测定，具体方法：用 孔径为 0.3μm 的微孔滤膜 过滤油分散性类胡萝卜素制剂，收集油中的微粒，再加入水使微粒分散，取水相样品进行激光粒度仪检测。
本发明的优点是 油分散性类胡萝卜素制剂 中类胡萝卜素颗粒表面有致密的水溶性胶体层保护而稳定性高，并且能制备 类胡萝卜素含量高达 2% ～ 14% 和平均粒径仅为 0.1 ～ 1μm 的 油分散性类胡萝卜素制剂 ，实用性强。
图 1 为实施例 1 制备的油分散性虾青素制剂的光学显微照片，放大倍率 200 倍。
图 2 为对比例制备的油分散性虾青素制剂的光学显微照片，放大倍率 200 倍。
图 3 为实施例 1 制备的油分散性虾青素制剂 A 与对比例制备的油分散性虾青素制剂 B 的热稳定性比较。
实施例 1
将 20g 虾青素粗结晶溶于 3L 二氯甲烷，制成虾青素溶液；以喷雾形式将虾青素溶液缓慢加入到含 20L 乙醇的釜中，调节喷雾速度，使析出的无定形虾青素粒子粒径小于 2μm ；喷完后用孔径为 0.3μm 的微孔滤膜过滤，滤饼经乙醇洗涤、压干，得超细化的虾青素粉末滤饼；将上述虾青素粉末滤饼与含 0.1g 维生素 C 、 89.4g 明胶的 1L 水溶液混合、搅拌打浆，再在高压均质器中均质 5 小时，乳化液先真空脱溶，再经喷雾干燥得 100g 虾青素微胶囊，其中含虾青素 10.5g 。
将 100g 虾青素微胶囊与含 0.2g 生育酚的 100g 大豆油混合，在氮气氛和 30 ℃下于胶体磨中研磨 3 次，制得均匀的油分散性虾青素制剂，其中含 5.0% 虾青素，虾青素平均粒径为 0.82μm 。
对比例
将 25.3g 虾青素粗结晶与含 0.1g 生育酚的 475g 大豆油混合，在氮气氛和 30 ℃下于胶体磨中研磨 3 次，制得均匀的油分散性虾青素制剂，其中含 5.0% 虾青素，虾青素平均粒径为 1.21μm 。
测试例
分别将实施例 1 制备的油分散性虾青素制剂与对比例制备的油分散性虾青素制剂于放大 200 倍的光学显微镜观测，得到图 1 和图 2 的显微镜照片。图 1 为实施例 1 制备的油分散性虾青素制剂的显微镜照片，表明虾青素存在明显的包埋材料包覆，油中的分散微粒平均粒径为 30.34μm ，取样过滤并用水分散，检测水相中虾青素的平均粒径为 0.82 μm ；图 2 为对比例制备的油分散性虾青素制剂的显微镜照片，虾青素以晶体形式存在，平均粒径为 1.21 μm 。
分别将实施例 1 制备的油分散性虾青素制剂与对比例制备的油分散性虾青素制剂于置于 90 ℃下进行加速分解试验，通过测定不同时间样品的虾青素的含量，比较稳定性的差异。如图 3 所示，横坐标为时间，纵坐标为用紫外光谱法测定的样品中虾青素含量， A 曲线代表实施例 1 制备的油分散性虾青素制剂， B 曲线代表对比例制备的油分散性虾青素制剂。对比例制备的油分散性虾青素制剂在加热 8 小时后开始显著降解，而实施例 1 制备的油分散性虾青素制剂 72 小时后虾青素含量仍未显著下降，表明实施例 1 制备的油分散性虾青素制剂热稳定性显著提高。
实施例 2
将 36.5kg β- 胡萝卜素结晶与 260kg 二氯甲烷在砂磨机中研磨，得平均粒径为 3μm 的 β- 胡萝卜素悬浮液；将 1kg 维生素 C 钠盐和 63.2kg 辛烯基琥珀酸淀粉酯溶于 200kg 水， 40 ℃保温备用。
将上述 β- 胡萝卜素悬浮液以 8kg / 小时的流量用浆料泵送入 4L 容积、具有 4 层搅拌的高径比为 4 的四段溶解釜的底部，同时以 200kg / 小时的流量将二氯甲烷经盘管预热器预热至 37 ℃后也送入溶解釜底部，控制釜内温度为 38 ℃，压力为 0.25Mpa ，停留时间约 15 分钟后取样分析，知已完成溶解成为 β- 胡萝卜素溶液；将上述 β- 胡萝卜素溶液和异丙醇（ 1000kg / 小时的流量）同时通入超重力旋转填充床析晶器中，控制转速为 3000 转 / 分钟，得到流量为 1200kg / 小时的 β- 胡萝卜素分散液；将上述 β- 胡萝卜素分散液在降膜蒸发器中减压脱除大部分溶剂，得到流量为 7kg/ 小时的 β- 胡萝卜素异丙醇分散液。
将上述 β- 胡萝卜素异丙醇分散液用泵以 7kg/ 小时的流量通入另一台超重力旋转填充床打浆器中，同时将已配好的辛烯基琥珀酸淀粉酯溶液以 27kg/ 小时的流量送入该超重力旋转填充床打浆器中，得到流量约为 35kg/ 小时的打浆液；将上述打浆液直接进行喷雾干燥，得 100kg β- 胡萝卜素微胶囊，其中含 β- 胡萝卜素 35.8kg 。
将 100kg β- 胡萝卜素微胶囊与含 1kg 乙氧喹啉的 150kg 玉米油混合，在氮气氛和 10 ℃下于胶体磨中研磨 5 次，制得均匀的油分散性 β- 胡萝卜素制剂，其中含 14.0%β- 胡萝卜素， β- 胡萝卜素平均粒径为 0.31μm 。
实施例 3
将 50g 角黄素粗结晶溶于 2L 氯仿，制成角黄素溶液；然后以喷雾形式将角黄素溶液缓慢加入到含 20L 95% 乙醇的釜中，调节喷雾速度，使析出的无定形角黄素粒子粒径小于 2μm ；喷完后用孔径为 0.3μm 的微孔滤膜过滤，滤饼经乙醇洗涤、压干，得超细化的角黄素粉末滤饼；将上述角黄素粉末滤饼与含 0.5g 异维生素 C 、 76.1g 阿拉伯胶的 1L 水溶液混合、搅拌打浆，再在高压均质器中均质 4 小时，乳化液先真空脱溶，再经喷雾干燥得 100g 角黄素微胶囊，其中含角黄素 23.4g 。
将 100g 角黄素微胶囊与含 0.4g BHT 的 300g 葵花籽油混合，在氮气氛和 20 ℃下于胶体磨中研磨 3 次，制得均匀的油分散性角黄素制剂，其中含 5.62% 角黄素，角黄素平均粒径为 0.83μm 。
实施例 4
将 15kg 番茄红素结晶与 120kg 二氯甲烷在砂磨机中研磨，得粒径为 3.6μm 的番茄红素悬浮液；将 0.3kg 异维生素 C 钠盐和 85.3kg 辛烯基琥珀酸淀粉酯溶于 200kg 水， 40 ℃保温备用。
将上述番茄红素悬浮液以 7kg/ 小时的流量用浆料泵送入 4L 容积、具有 4 层搅拌的高径比为 4 的四段溶解釜的底部，同时以 180kg/ 小时的流量将二氯甲烷经盘管预热器预热至 37 ℃后也送入溶解釜底部，控制釜内温度为 38 ℃，压力为 0.27Mpa ，停留时间约 12 分钟后取样分析，知已完成溶解成为番茄红素溶液；将上述番茄红素溶液和异丙醇（ 1000kg/ 小时的流量）同时通入超重力旋转填充床析晶器中，控制转速为 3000 转 / 分钟，得到流量为 1200kg / 小时的番茄红素分散液；将上述番茄红素分散液在降膜蒸发器中减压脱除大部分溶剂，得到流量为 7.5kg/ 小时的番茄红素异丙醇分散液。
将上述番茄红素异丙醇分散液用泵以 8kg/ 小时的流量通入另一台超重力旋转填充床打浆器中，同时将已配好的辛烯基琥珀酸淀粉酯溶液以 26kg/ 小时的流量送入该超重力旋转填充床打浆器中，得到流量约为 34kg/ 小时的打浆液；将上述打浆液直接进行喷雾干燥，得 100kg 番茄红素微胶囊，其中含番茄红素 14.4kg 。
将 100kg 番茄红素微胶囊与含 0.2kg TBHQ 的 200kg 花生油混合，在氮气氛和 20 ℃下于胶体磨中研磨 3 次，制得均匀的油分散性番茄红素制剂，其中含 4.62% 番茄红素，番茄红素平均粒径为 0.10μm 。
实施例 5
将 40g 叶黄素粗结晶溶于 2L 氯仿，制成叶黄素溶液；然后以喷雾形式将叶黄素溶液缓慢加入到含 20L 乙醇的釜中，调节喷雾速度，使析出的无定形叶黄素粒子粒径小于 2μm ；喷完后用孔径为 0.3μm 的微孔滤膜过滤，滤饼经乙醇洗涤、压干，得超细化的叶黄素粉末滤饼；将上述叶黄素粉末滤饼与含 0.3g 异维生素 C 、 83.3g 阿拉伯胶的 1L 水溶液混合、搅拌打浆，再在高压均质器中均质 4 小时，乳化液先真空脱溶，再经喷雾干燥得 100g 叶黄素微胶囊，其中含叶黄素 16.4g 。
将 100g 叶黄素微胶囊与含 0.5g BHT 的 350g 色拉油混合，在氮气氛和 25 ℃下于胶体磨中研磨 4 次，制得均匀的油分散性叶黄素制剂，其中含 3.61% 叶黄素，叶黄素平均粒径为 0.73μm 。
实施例 6
将 20g 虾青素粗结晶溶于 3L 二氯甲烷，制成虾青素溶液；以喷雾形式将虾青素溶液缓慢加入到含 20L 乙醇的釜中，调节喷雾速度，使析出的无定形虾青素粒子粒径小于 2μm ；喷完后用孔径为 0.3μm 的微孔滤膜过滤，滤饼经乙醇洗涤、压干，得超细化的虾青素粉末滤饼；将上述虾青素粉末滤饼与含 0.1g 维生素 C 、 89.4g 明胶的 1L 水溶液混合、搅拌打浆，再在高压均质器中均质 5 小时，乳化液先真空脱溶，再经喷雾干燥得 100g 虾青素微胶囊，其中含虾青素 10.5g 。
将 100g 虾青素微胶囊与含 0.1g 生育酚的 400g 大豆油混合，在氮气氛和 30 ℃下于胶体磨中研磨 1 次，制得均匀的油分散性虾青素制剂，其中含 2.1% 虾青素，虾青素平均粒径为 1.00μm。

Claims (5)

  1. 一种油分散性类胡萝卜素制剂的制备方法，其特征在于：以重量份计，包括以下步骤：
    将 100 份类胡萝卜素微胶囊与 100 ～ 400 份植物油、 0.1 ～ 1 份抗氧化剂 B 混合，在氮气氛和 10 ～ 30 ℃下于胶体磨中研磨，制得均匀的油分散性类胡萝卜素制剂，其中类胡萝卜素颗粒平均粒径为 0.1 ～ 1μm ；
    所述的 100 份类胡萝卜素微胶囊中含 10.5 ～ 35.8 份类胡萝卜素、 0.1 ～ 1 份抗氧化剂 A ，其余为水溶性胶体；
    所述的抗氧化剂 A 为维生素 C 、维生素 C 钠盐、异维生素 C 或异维生素 C 钠盐；
    所述的抗氧化剂 B 为生育酚、乙氧喹啉、 BHT 或 TBHQ 。
  2. 根据权利要求1所述的油分散性类胡萝卜素制剂的制备方法，其特征在于，所述的类胡萝卜素为β-胡萝卜素、虾青素、番茄红素、角黄素或叶黄素。
  3. 根据权利要求1所述的油分散性类胡萝卜素制剂的制备方法，其特征在于，所述的水溶性胶体为明胶、辛烯基琥珀酸淀粉酯或阿拉伯胶。
  4. 根据权利要求1所述的油分散性类胡萝卜素制剂的制备方法，其特征在于，所述的植物油为大豆油、玉米油、葵花籽油、花生油或色拉油。
  5. 根据权利要求1-4任一权利要求所述的油分散性类胡萝卜素制剂的制备方法制备的油分散性类胡萝卜素制剂。
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