WO2012129765A1 - 一种连续化稳定维生素a微胶囊的制备方法 - Google Patents

一种连续化稳定维生素a微胶囊的制备方法 Download PDF

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WO2012129765A1
WO2012129765A1 PCT/CN2011/072190 CN2011072190W WO2012129765A1 WO 2012129765 A1 WO2012129765 A1 WO 2012129765A1 CN 2011072190 W CN2011072190 W CN 2011072190W WO 2012129765 A1 WO2012129765 A1 WO 2012129765A1
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Prior art keywords
vitamin
modified starch
microcapsules
packed bed
emulsifier
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English (en)
French (fr)
Inventor
尹红
陈建峰
陈志荣
王洁欣
祁勇
赵宏
石立芳
仇丹
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Beijing University of Chemical Technology
Zhejiang University ZJU
Zhejiang NHU Co Ltd
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Beijing University of Chemical Technology
Zhejiang University ZJU
Zhejiang NHU Co Ltd
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Priority to PCT/CN2011/072190 priority Critical patent/WO2012129765A1/zh
Priority to US13/980,126 priority patent/US9173818B2/en
Publication of WO2012129765A1 publication Critical patent/WO2012129765A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
    • 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
    • A61K31/07—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
    • A61K9/1629—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
    • A61K9/1682—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
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; 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
    • A61K9/48—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
    • 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
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • 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

Definitions

  • the invention relates to a preparation method for continuously stabilizing vitamin A microcapsules, in particular to the preparation of a continuous stabilized vitamin A microcapsule by using a supergravity rotary packed bed emulsifier.
  • Vitamin A is a fat-soluble vitamin that is easily soluble in organic solvents and fats and insoluble in water. Vitamin A is easy to deteriorate when it is exposed to light, heat, acid or oxidant, so it is generally necessary to make it into microcapsule form.
  • the microencapsulation of vitamin A is usually carried out by first heating and emulsifying the vitamin A crystal, the oil and the aqueous solution containing the protective colloid, and then spray-drying the emulsion to obtain a book.
  • Chinese patent CN1965657(A) describes a method for preparing vitamin A microcapsules, which adds vitamin A oil to a pre-formulated modified starch solution several hours ago, and disperses at a high speed at 5,000 to 20,000 rpm, and then The mixture was homogenized twice at room temperature, 10 to 40 MPa, and finally spray-dried to obtain vitamin A microcapsules. Due to the fine particle size of the obtained product, it is mainly used for the strengthening of flour.
  • Chinese patent CN101214219(A) reports the preparation of vitamin A and vitamin E microcapsules.
  • the emulsification process uses high-speed shearing at 10,000 ⁇ 20500 rpm, and it needs to be homogenized 3 times at 40-60 MPa, and then spray-dried. Microcapsules.
  • the emulsification process is carried out in batches and in an open environment, the emulsification time of a single batch is long, and the temperature of the shearing portion during emulsification is high, which easily deteriorates vitamin A;
  • the emulsion Due to the batch operation, the emulsion is easy to stratify during the spray drying process after the emulsification is completed, and the aggregated vitamin A small oil beads are easily aggregated into large particles, thereby affecting the embedding effect and bioavailability of the final product.
  • High-pressure homogenization method is difficult to disperse vitamin A in micro-capsules in nanometer size, thus affecting the use in some products.
  • the inventors have proposed a method for preparing a continuous nanodispersed vitamin A microcapsule in CN101513394A.
  • the method firstly grinds the vitamin A crystal with an antioxidant and a solvent to form a vitamin A dispersion, and then uses a pump to preheat the solution to be dissolved, then cooled, and then sent to a supergravity rotary bed crystallizer, which will contain
  • the aqueous solution of the protective colloid is sent to the same supergravity rotating bed crystallizer, and the nano-dispersed vitamin A dispersion is obtained at the outlet, and the dispersion is fluidized.
  • the spray dryer of the cooling device is spray-dried to obtain nano-dispersed vitamin A microcapsules.
  • the invention adopts a supergravity rotary bed crystallizer as a means for nanometering of vitamin A, so that the bioavailability of vitamin A is improved, and the application surface of the product is expanded.
  • vitamin A is a fat-soluble and poorly stable vitamin. Even if it is microencapsulated by spray drying, its effective content will be significantly reduced due to the influence of light, heat, oxidant and acid during storage. Through further research, we found that if we can avoid prolonged heating during the microencapsulation of vitamin A, minimize the chance of contact with oxygen, and increase the oxygen barrier and water blocking measures of the outer layer of microcapsules, it can effectively improve Vitamin A stability.
  • the object of the present invention is to address the deficiencies of prior art vitamin A microcapsule production techniques.
  • the present invention provides a process for the preparation of a continuously produced stable vitamin A microcapsule.
  • the preparation method of the continuous stable vitamin A microcapsule comprises the following steps:
  • the vitamin A crystal and antioxidant are continuously added to the crystallizer at a weight ratio of 100: 1-5, and melted at 65 to 75 ° C to prepare a vitamin A melt containing an antioxidant;
  • the vitamin A emulsion is continuously atomized and sprayed into a cooled starch bed for granulation, and then fluidized and dried at 65 to 75 ° C in a fluidized bed using nitrogen as a drying medium. That is, stable vitamin A microcapsules are obtained.
  • the antioxidant is ethoxyquinoline, tocopherol, BHT or BHA.
  • the supergravity rotary packed bed emulsifier has a liquid distributor with a wire mesh and a rotational speed of 1500-2500 rpm.
  • the gelatinized modified starch is used as the main embedding material, and then spray granulation, fluidized drying and gelation treatment, so that the product has a double-layer protection effect, and the embedding effect is good, and it is not easy to suck.
  • the vitamin A crystal was added to a special crystallizer at 0 kgg/hr and the antioxidant ethoxyquinoline at 0.5 kg/hr, and the crystal was melted at 65 ° C to obtain 10.5 Kg/hr of vitamin A. Melt oil.
  • the gelatinizable modified starch 567 Kg was dissolved in 1323 Kg of 65 ° C water to prepare a 30% modified starch aqueous solution, and degassed at -0.08 MPa for 2 hours.
  • the above-mentioned vitamin A melt oil was pumped at a flow rate of 10.5 Kg/hour into a supergravity rotary packed bed emulsifier with a liquid distributor and a rotation speed of 1500 rpm, and the modified starch aqueous solution after deoxidation was 94.5.
  • the Kg/hour flow was fed into the same supergravity rotary packed bed emulsifier and the vitamin A emulsion was obtained from the outlet.
  • the above vitamin A emulsion was continuously sprayed into a cooled starch bed to be granulated, and after 20 hours, about 2800 Kg of wet vitamin A microcapsules were obtained.
  • the above wet vitamin A microcapsules were transferred to a fluidized bed, fluidized and dried by gelation with hot nitrogen at 65 ° C, and finally 1010 Kg of vitamin A microcapsules were obtained.
  • the content of vitamin A was 19.62% and the yield of microencapsulation was 99.08% by HPLC analysis. After 2 years of storage at room temperature, the content was 19.05%, and the vitamin A retention rate was 97.1%.
  • the gelatinizable modified starch is CAPSUL 2330 manufactured by National Starch.
  • vitamin A crystals were added to a special crystallizer at 0 kg/hr, and antioxidant tocopherol at 0.3 kg/hour, and the crystals were melted at 70 ° C to obtain 10.3 Kg/hr of vitamin A melt.
  • the gelatinizable modified starch 247.2 Kg was dissolved in 370.8 kg of 75 ° C water to prepare a 40% modified starch aqueous solution, and degassed at -0.07 MPa for 1 hour.
  • the above-mentioned vitamin A melt oil was pumped at a flow rate of 10.3 Kg/hour into a supergravity rotary packed bed emulsifier with a liquid distributor and a rotation speed of 2500 rpm, and the modified starch aqueous solution after deoxidation was 30.9.
  • the Kg/hour flow was fed into the same supergravity rotary packed bed emulsifier and the vitamin A emulsion was obtained from the outlet.
  • the above vitamin A emulsion was continuously atomized and sprayed into a cooled starch bed to be granulated, and after 20 hours, about 1,100 Kg of wet vitamin A microcapsules were obtained.
  • the above wet vitamin A microcapsules were transferred to a fluidized bed and fluidized and dried with hot nitrogen at 75 °C. And gelation treatment, finally obtained 548Kg vitamin A microcapsules.
  • the content of vitamin A was 36.05%, and the yield of microencapsulation was 98.78%.
  • the content was 34.72%, and the vitamin A retention rate was 96.3%.
  • the vitamin A crystal was added to a special crystallizer at 10 Kg/hr, the antioxidant BHT at 0.05 Kg/hr, and the BHA at 0.05 Kg/hr, and the crystal was melted at 75 ° C to obtain 10.1 Kg/ Hour vitamin A melt oil.
  • the gelatinizable modified starch 424.2 Kg was dissolved in 787.8 Kg of 70 ° C water to prepare a 35% modified starch aqueous solution, and degassed at -0.075 MPa for 1.5 hours.
  • the above-mentioned vitamin A melt oil was pumped at a flow rate of 10.1 Kg/hour into a supergravity rotary packed bed emulsifier with a liquid distributor and a rotation speed of 2000 rpm, and the modified starch aqueous solution after deoxidation was 60.6.
  • the Kg/hour flow is fed into the same supergravity rotary packed bed emulsifier, and the vitamin A emulsion is obtained from the outlet.
  • the above vitamin A emulsion was continuously sprayed into a cooled starch bed to be granulated, and after 20 hours, about 1800 Kg of wet vitamin A microcapsules were obtained.
  • the above wet vitamin A microcapsules were transferred to a fluidized bed, fluidized and dried by a hot nitrogen gas at 70 ° C, and gelatinized, and finally 776 Kg of vitamin A microcapsules were obtained.
  • the content of vitamin A was 25.53%, and the yield of microencapsulation was 99.06%.
  • the content was 24.69%, and the retention rate of vitamin A was 96.7%.
  • the ordinary modified starch 567Kg and 260Kg dextrin were dissolved in 1930Kg of 65 ° C water to prepare a 30% modified starch aqueous solution.
  • the modified starch aqueous solution was placed in an emulsification kettle equipped with a high-speed shear emulsifier, and the above-mentioned vitamin A melt oil was added to an emulsified kettle under high-speed shearing, and the mixture was emulsified for 1 hour. Then, the above emulsion was spray-dried at a flow rate of 300 kg/hr under a slow shearing condition, and sprayed after 9.9 hours. Finally, 1006 kg of vitamin A microcapsules were obtained. According to HPLC analysis, it contained vitamin A 18.86%, and the microencapsulation yield was 94.89%. After 2 years of storage at room temperature, the content was 17.07%, and the retention rate of vitamin A was 90.5%.
  • the modified starch aqueous solution was placed in an emulsification kettle equipped with a high-speed shear emulsifier, and the above-mentioned vitamin A melt oil was added to an emulsified kettle under high-speed shearing, and the mixture was emulsified for 1 hour. Then, the above emulsion was spray-dried at a flow rate of 300 kg/hr under a slow shearing condition, and sprayed after 3.7 hours. Finally, 550 kg of vitamin A microcapsules were obtained. According to HPLC analysis, it contained vitamin A34.62%, and the microencapsulation yield was 95.20%. After 2 years of storage at room temperature, the content was 30.88% and the vitamin A retention rate was 89.2%.
  • the ordinary modified starch 424.2Kg and 180Kg dextrin were dissolved in 1122Kg of 70 ° C water to prepare a 35% modified starch aqueous solution.
  • the modified starch aqueous solution was placed in an emulsification kettle equipped with a high-speed shear emulsifier, and the above-mentioned vitamin A melt oil was added to the emulsified kettle under high-speed shearing, and the mixture was emulsified for 1 hour. Then, the above emulsion was spray-dried at a flow rate of 300 kg/hr under a slow shearing condition, and sprayed after 6.4 hours. Finally, 780Kg of vitamin A microcapsules were obtained. According to HPLC analysis, it contained vitamin A24.49%, and the microcapsule yield was 95.52%. After 2 years of storage at room temperature, the content was 22.24% and the vitamin A retention rate was 90.8%.

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Description

一种连续化稳定维生素 A微胶囊的制备方法
技术领域
本发明涉及一种连续化稳定维生素 A微胶囊的制备方法， 具体涉及采用超 重力旋转填充床乳化器进行连续化稳定维生素 A微胶囊的制备。
背景技术
维生素 A是一种脂溶性维生素， 易溶于有机溶剂和脂肪， 不溶于水。 维生 素 A遇光、 热、 酸、 氧化剂时均易变质， 故一般需将其制成微胶囊形式才能使 说
用。
维生素 A的微胶囊化通常是先将维生素 A结晶、 配油与含保护胶体的水溶 液一起加热、 乳化， 再将乳液喷雾干燥得到书。
中国专利 CN1965657(A)介绍了一种制备维生素 A微胶囊的方法，该方法将 维生素 A油加入到几小时前预先配制好的改性淀粉溶液中， 在 5000~20000rpm 转速下高速分散乳化， 然后在室温、 10~40MPa下均质两次， 最后离心喷雾干燥 得到维生素 A微胶囊。 由于所得产品粒径细， 主要用于面粉的强化。
中国专利 CN101214219(A)则报道了制备维生素 A、维生素 E微胶囊的方法， 其乳化过程用到了 10000~20500rpm的高速剪切， 并且需在 40~60MPa下均质 3 次， 而后经喷雾干燥制备微胶囊。
上述高速剪切乳化加高压均质， 然后经喷雾干燥制备维生素 A微胶囊的方 法存在以下难以克服的问题：
1)乳化过程分批进行且在敞开环境中， 单批乳化时间长，乳化时剪切部位温 度高， 易使维生素 A变质；
2)高速剪切机和高压均质机所需电机功率大， 能耗高；
3)由于分批操作，乳化完成后在喷雾干燥过程中乳液易分层， 聚集的维生素 A小油珠易聚并成大颗粒， 从而影响最终产品的包埋效果和生物利用度。
4)高压均质方法难以使维生素 A 以纳米级尺寸分散于微胶囊中， 从而影响 到了在一些产品中的使用。
针对上述问题， 发明人已在 CN101513394A中提出了一种连续化纳米分散 维生素 A微胶囊的制备方法。 该法先将维生素 A晶体与抗氧化剂、 溶剂一起研 磨配成维生素 A分散液， 然后用泵将上述分散液经预热升温溶解后冷却， 再送 入超重力旋转床析晶器中， 同时将含有保护胶体的水溶液送入同一超重力旋转 床析晶器中， 出口得到纳米分散的维生素 A分散液， 将该分散液在带有流态化 冷却装置的喷雾干燥器中喷雾干燥， 即得到纳米分散的维生素 A微胶囊。 该发 明采用超重力旋转床析晶器作为维生素 A纳米化的手段， 使得维生素 A的生物 利用度提高， 产品适用面扩大。
但维生素 A是一种脂溶性、稳定性差的维生素， 即使经喷雾干燥微胶囊化， 在产品的贮存中， 由于受光、 热、 氧化剂、 酸的影响， 其有效含量仍会明显下 降。 通过进一步的研究， 我们发现， 如果能在维生素 A的微胶囊化过程中避免 长时间受热， 尽量减少与氧的接触机会， 同时增加微胶囊外层的阻氧、 阻水措 施， 则可有效提高维生素 A的稳定性。
发明内容
本发明的目的是针对现有维生素 A微胶囊生产技术的不足之处， 本发明提 供一种可连续生产的稳定维生素 A微胶囊的制备方法。
连续化稳定维生素 A微胶囊的制备方法包括以下步骤：
1)在氮气保护下， 将维生素 A结晶、抗氧化剂按 100: 1-5的重量比例连 续加入结晶熔化器中， 于 65~75°C熔化， 配成含抗氧剂的维生素 A熔油；
2)将可凝胶化改性淀粉溶于 65~75°C水中， 配成 30~40%改性淀粉水溶液， 并于 -0.07 0.08MPa真空下除氧 1~2小时；
3)将维生素 A熔油用泵送入带有液体分布器的超重力旋转填充床乳化器中； 同时， 将除氧后的改性淀粉水溶液用泵送入同一超重力旋转填充床乳化器中， 在出口得到维生素 A乳化液， 维生素 A熔油与改性淀粉水溶液的重量比为 1 : 3-9；
4)将维生素 A乳化液连续雾化喷入冷却的淀粉床中进行造粒， 然后在以氮 气作为干燥介质的流化床中于 65~75°C进行流态化干燥、凝胶化处理， 即得到稳 定维生素 A微胶囊。
所述的抗氧化剂为乙氧基喹啉、 生育酚、 BHT或 BHA。
所述超重力旋转填充床乳化器带有液体分布器， 填料为金属丝网， 转速为 1500-2500转 /分钟。
本发明与现有技术相比具有的有益效果：
1)采用可凝胶化改性淀粉为主要包埋材料，再经喷雾造粒、流态化干燥及凝 胶化处理， 因而对产品产生了双层保护作用， 其包埋效果好， 不易吸潮；
2)采用超重力旋转填充床乳化器连续乳化， 乳液中维生素 A微粒尺寸均匀， 避免了生物利用度低的大晶体的产生；
3)生产过程充分的氮气保护及除氧措施保证了生产过程中维生素 A不变质， 这样不仅微胶囊化过程收率高， 同时也增加了产品的贮存稳定性。 下面结合实施例对本发明予以详细说明。
具体实施方式
实施例 1
在氮气保护下，将维生素 A结晶以 lOKg/小时、抗氧剂乙氧基喹啉以 0.5Kg/ 小时加入特制的结晶熔化器中，于 65°C使结晶熔化，得到 10.5 Kg/小时维生素 A 熔油。
将可凝胶化改性淀粉 567Kg溶于 1323Kg65 °C水中，配成 30%改性淀粉水溶 液， 并于 -0.08MPa脱气 2小时。
将上述维生素 A熔油用泵以 10.5 Kg/小时流量送入带有液体分布器、 转速 为 1500转 /分钟的超重力旋转填充床乳化器中，同时将除氧后的改性淀粉水溶液 以 94.5 Kg/小时流量送入同一超重力旋转填充床乳化器中，从出口得到维生素 A 乳化液。
将上述维生素 A乳化液连续雾化喷入冷却的淀粉床中造粒， 经 20小时后， 得到约 2800 Kg湿的维生素 A微胶囊。
将上述湿的维生素 A微胶囊转到流化床中， 用 65 °C热氮气进行流态化干燥 及凝胶化处理， 最后得到 1010 Kg维生素 A微胶囊。 经 HPLC分析， 其中维生 素 A的含量为 19.62%，微胶囊化收率为 99.08%。常温贮存 2年后，含量为 19.05%， 维生素 A保留率为 97.1%。
可凝胶化改性淀粉为 National Starch (美国国民淀粉有限公司）生产的 CAPSUL 2330。
实施例 2
在氮气保护下， 将维生素 A结晶以 lOKg/小时、 抗氧剂生育酚以 0.3Kg/小 时加入特制的结晶熔化器中， 于 70°C使结晶熔化， 得到 10.3 Kg/小时维生素 A 熔油。
将可凝胶化改性淀粉 247.2Kg溶于 370.8Kg75°C水中，配成 40%改性淀粉水 溶液， 并于 -0.07MPa脱气 1小时。
将上述维生素 A熔油用泵以 10.3 Kg/小时流量送入带有液体分布器、 转速 为 2500转 /分钟的超重力旋转填充床乳化器中，同时将除氧后的改性淀粉水溶液 以 30.9 Kg/小时流量送入同一超重力旋转填充床乳化器中，从出口得到维生素 A 乳化液。
将上述维生素 A乳化液连续雾化喷入冷却的淀粉床中造粒， 经 20小时后， 得到约 1100 Kg湿的维生素 A微胶囊。
将上述湿的维生素 A微胶囊转到流化床中， 用 75 °C热氮气进行流态化干燥 及凝胶化处理， 最后得到 548Kg维生素 A微胶囊。 经 HPLC分析， 其中维生素 A的含量为 36.05%,微胶囊化收率为 98.78%。常温贮存 2年后，含量为 34.72%, 维生素 A保留率为 96.3%。
实施例 3
在氮气保护下， 将维生素 A结晶以 10Kg/小时、 抗氧剂 BHT以 0.05Kg/小 时、 BHA以 0.05Kg/小时加入特制的结晶熔化器中， 于 75°C使结晶熔化， 得到 10.1 Kg/小时维生素 A熔油。
将可凝胶化改性淀粉 424.2Kg溶于 787.8Kg70°C水中，配成 35%改性淀粉水 溶液， 并于 -0.075MPa脱气 1.5小时。
将上述维生素 A熔油用泵以 10.1 Kg/小时流量送入带有液体分布器、 转速 为 2000转 /分钟的超重力旋转填充床乳化器中，同时将除氧后的改性淀粉水溶液 以 60.6Kg/小时流量送入同一超重力旋转填充床乳化器中， 从出口得到维生素 A 乳化液。
将上述维生素 A乳化液连续雾化喷入冷却的淀粉床中造粒， 经 20小时后， 得到约 1800 Kg湿的维生素 A微胶囊。
将上述湿的维生素 A微胶囊转到流化床中， 用 70 °C热氮气进行流态化干燥 及凝胶化处理， 最后得到 776 Kg维生素 A微胶囊。 经 HPLC分析， 其中维生素 A的含量为 25.53% ,微胶囊化收率为 99.06%。常温贮存 2年后，含量为 24.69%, 维生素 A保留率为 96.7%。
比较例 1
将 200Kg维生素 A结晶、 10Kg乙氧基喹啉投入熔油釜中， 于 65 °C使结晶 熔化， 得到 210Kg维生素 A熔油。
将普通改性淀粉 567Kg和 260Kg糊精溶于 1930Kg65°C水中， 配成 30%改 性淀粉水溶液。
将上述改性淀粉水溶液投入装有高速剪切乳化机的乳化釜中， 在高速剪切 下将上述维生素 A熔油加入乳化釜中， 加毕， 再剪切乳化 1小时。 然后在慢速 剪切条件下，将上述乳化液以 300Kg/小时的流量进行喷雾干燥， 9.9小时后喷完。 最后得到 1006Kg维生素 A微胶囊。 经 HPLC分析， 其中含维生素 A18.86%， 微胶囊化收率为 94.89%。常温贮存 2年后， 含量为 17.07%, 维生素 A保留率为 90.5%。
比较例 2
将 200Kg维生素 A结晶、 6Kg生育酚投入熔油釜中， 于 70°C使结晶熔化， 得到 206Kg维生素 A熔油。 将普通改性淀粉 247.2Kg和 115Kg糊精溶于 543Kg75 °C水中， 配成 40%改 性淀粉水溶液。
将上述改性淀粉水溶液投入装有高速剪切乳化机的乳化釜中， 在高速剪切 下将上述维生素 A熔油加入乳化釜中， 加毕， 再剪切乳化 1小时。 然后在慢速 剪切条件下，将上述乳化液以 300Kg/小时的流量进行喷雾干燥， 3.7小时后喷完。 最后得到 550Kg维生素 A微胶囊。 经 HPLC分析， 其中含维生素 A34.62%， 微 胶囊化收率为 95.20%。 常温贮存 2年后， 含量为 30.88% , 维生素 A保留率为 89.2%。
比较例 3
将 200Kg维生素 A结晶、 lKgBHT和 lKgBHA投入熔油釜中， 于 75°C使 结晶熔化， 得到 202Kg维生素 A熔油。
将普通改性淀粉 424.2Kg和 180Kg糊精溶于 1122Kg70°C水中，配成 35%改 性淀粉水溶液。
将上述改性淀粉水溶液投入装有高速剪切乳化机的乳化釜中， 在高速剪切下将 上述维生素 A熔油加入乳化釜中， 加毕， 再剪切乳化 1小时。 然后在慢速剪切 条件下， 将上述乳化液以 300Kg/小时的流量进行喷雾干燥， 6.4小时后喷完。 最 后得到 780Kg维生素 A微胶囊。 经 HPLC分析， 其中含维生素 A24.49%， 微胶 囊化收率为 95.52%。常温贮存 2年后，含量为 22.24% ,维生素 A保留率为 90.8%。

Claims

权 利 要 求 书
1.一种连续化稳定维生素 A微胶囊的制备方法， 其特征在于包括以下步骤:
1)在氮气保护下， 将维生素 A结晶、抗氧化剂按 100: 1-5的重量比例连 续加入结晶熔化器中， 于 65~75°C熔化， 配成含抗氧剂的维生素 A熔油；
2)将可凝胶化改性淀粉溶于 65~75°C水中， 配成 30~40%改性淀粉水溶液， 并于 -0.07 0.08MPa真空下除氧 1~2小时；
3)将维生素 A熔油用泵送入带有液体分布器的超重力旋转填充床乳化器中； 同时， 将除氧后的改性淀粉水溶液用泵送入同一超重力旋转填充床乳化器中， 在出口得到维生素 A乳化液， 维生素 A熔油与改性淀粉水溶液的重量比为 1 : 3-9；
4)将维生素 A乳化液连续雾化喷入冷却的淀粉床中进行造粒， 然后在以氮 气作为干燥介质的流化床中于 65~75°C进行流态化干燥、凝胶化处理， 即得到稳 定维生素 A微胶囊。
2.根据权利要求 1所述的一种连续化稳定维生素 A微胶囊的制备方法， 其 特征是所述的抗氧化剂为乙氧基喹啉、 生育酚、 BHT或 BHA。
3.根据权利要求 1所述的一种连续化稳定维生素 A微胶囊的制备方法， 其 特征是所述超重力旋转填充床乳化器带有液体分布器， 填料为金属丝网， 转速 为 1500~2500转 /分钟。
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