WO2023083097A1 - 一种颗粒型酶制剂的热熔包被方法及其应用 - Google Patents

一种颗粒型酶制剂的热熔包被方法及其应用 Download PDF

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WO2023083097A1
WO2023083097A1 PCT/CN2022/129636 CN2022129636W WO2023083097A1 WO 2023083097 A1 WO2023083097 A1 WO 2023083097A1 CN 2022129636 W CN2022129636 W CN 2022129636W WO 2023083097 A1 WO2023083097 A1 WO 2023083097A1
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hot
temperature
melting point
melt coating
coating method
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PCT/CN2022/129636
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English (en)
French (fr)
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刘明娜
邓启生
王海燕
李阳
陈凯
张广民
蔡辉益
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天津博菲德科技有限公司
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Publication of WO2023083097A1 publication Critical patent/WO2023083097A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/189—Enzymes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A61K38/443—Oxidoreductases (1) acting on CH-OH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • 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
    • A61K9/501—Inorganic compounds
    • 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
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y101/00—Oxidoreductases acting on the CH-OH group of donors (1.1)
    • C12Y101/03—Oxidoreductases acting on the CH-OH group of donors (1.1) with a oxygen as acceptor (1.1.3)
    • C12Y101/03004—Glucose oxidase (1.1.3.4)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/03—Phosphoric monoester hydrolases (3.1.3)
    • C12Y301/03008—3-Phytase (3.1.3.8)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/03—Phosphoric monoester hydrolases (3.1.3)
    • C12Y301/03026—4-Phytase (3.1.3.26), i.e. 6-phytase
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P60/00—Technologies relating to agriculture, livestock or agroalimentary industries
    • Y02P60/80—Food processing, e.g. use of renewable energies or variable speed drives in handling, conveying or stacking
    • Y02P60/87—Re-use of by-products of food processing for fodder production

Definitions

  • the invention relates to the field of enzyme preparation processing, in particular to a hot-melt coating method of granular enzyme preparation and its application
  • Enzyme is a kind of biological catalyst, and like other proteins, it is sensitive to factors such as temperature, humidity, and metal ions.
  • Feed enzyme preparations are mostly produced by liquid fermentation. Fermented strains are fermented to obtain fermentation broth. Different post-treatment processes can be used to obtain enzyme preparation products in different formulations, including liquid enzymes, powder enzymes, common granule enzymes and coated enzymes.
  • the coated granzyme has the best stability, because there is a firm and easily soluble film coating on its surface, which isolates the enzyme granules from the outside world and is more conducive to the stability of the enzyme.
  • Pelletizing and extruding processes are often used in pellet feed processing, because they are carried out under high temperature and high humidity conditions, which will have a great impact on enzyme activity.
  • Hot-melt coating refers to covering the coating material on the surface of the substrate in a molten state and then cooling and solidifying to form a coating film to block the influence of high temperature and high humidity on the substrate.
  • the hot melt coating process differs from conventional coating techniques in that it does not use solvents.
  • the traditional hot-melt coating process needs to melt the coating material in advance and cover the surface of the substrate through a spraying device. Therefore, in order to form a high-quality coating film, the temperature of the material must be kept close to the freezing point of the coating solution during the coating process.
  • the invention develops a hot-melt coating method suitable for enzyme preparations.
  • the hot-melt coating method in the present invention comprises that the pellet core containing enzyme and the coating material composed of low melting point lipid material and inert material are evenly mixed according to the mass ratio of 100: (8-10) and placed in a place where the content can be heated by hot air In a closed device with stable temperature control, heat and induce wind, the system temperature reaches 65-70°C and maintains for 30-40min, then slowly cools down.
  • the airtight device capable of stable temperature control is preferably a fluidized bed or an ebullated bed.
  • the method includes:
  • Step 1 Mix the enzyme powder preparation, starch, sodium bicarbonate, monoglyceride, and water evenly to prepare a soft material.
  • the mass percentage of each component enzyme preparation 16%-20%, starch 35%-40%, Yuanming powder 13%-18%, monoglyceride 0.5%-2%, water 20%-35%; preferably, The mass percentage of each component: 16% of enzyme preparation, 37% of starch, 18% of sodium glutamate, 2% of monoglyceride, and 27% of water.
  • Step 2 Make the prepared soft material into pellets through a swing granulator.
  • Step 3 drying the pellets in step 2 to obtain pellet cores, the condition is that the material temperature is 40-45° C., and the drying time is controlled at 40-60 minutes; preferably, the drying is carried out in a fluidized bed.
  • step 3 is used to obtain the pellet core of 30-60 mesh size particles
  • the hot-melt coating material includes a low-melting point lipid material and an inert material, and the mass ratios are 80%-90% and 10%-20% respectively; wherein, the low-melting point lipid The melting point of the material is ⁇ 65°C.
  • the low-melting point lipid material is any one or a mixture of two or more in any proportion of glyceryl stearate, stearic acid, hydrogenated oil, and paraffin;
  • the inert material is calcium carbonate, sulfuric acid Any one of calcium, talc, kaolin or a mixture of two or more in any proportion.
  • Step 5 Mix the pellet core obtained in step 3 with the hot-melt coating material obtained in step 4 in a mass ratio of 100: (8-10) and place it in a closed device, turn on the heating, introduce air, and put the air into the Set the temperature to 65-70°C. When the temperature of the material reaches 65-70°C, continue heating for 30-40 minutes to ensure that the low melting point lipid material is completely melted;
  • Step 6 Turn off the heating, keep the induced draft and continue to turn on, and the temperature in the airtight device will cool down slowly.
  • the temperature is lower than the melting point of the low-melting point lipid material, the low-melting point lipid material will start to solidify and form on the surface of the enzyme preparation pellet core. A tight hydrophobic layer to obtain hot-melt coated enzyme preparation products.
  • the present invention also provides an enzyme preparation prepared by the hot-melt coating method of the aforementioned enzyme preparation.
  • the present invention also provides an application of the aforementioned enzyme preparation hot-melt coating method in the field of feed enzyme preparations, wherein the feed enzyme preparations include but not limited to phytase, glucose oxidase, protease and other feed enzyme preparations.
  • the coating material and the pellet core are placed in a closed device at the same time, and the temperature is raised at the same time, the coating time is shortened to one-fifth of the traditional hot-melt coating process, and the method has mild conditions and high repeatability.
  • the coating of the coated enzyme preparation particles has good airtightness, low requirements on equipment (no spray gun, atomizer and other equipment are required), there is no safety hazard between the heated coating material and the hot air, it is not easy to burn in actual operation, and the operation steps are simple ;
  • the enzyme activity retention rate after coating can be significantly improved, and the heat-resistant performance (enzyme activity retention rate after heat-resistant treatment) of the hot-melt coated enzyme preparation is increased to more than ten times the original.
  • Embodiment 1 the comparative study of different coating processes on the coating effect of high-yield glucose oxidase preparation for feed 1, coating process steps:
  • Step 1 Mix the enzyme powder preparation, starch, sodium bicarbonate, monoglyceride, and water evenly to prepare a soft material. Wherein the mass percentage of each component: 16% of enzyme preparation, 37% of starch, 18% of sodium glutamate, 2% of monoglyceride, 27% of water;
  • Step 2 Make the prepared soft material into pellets with a size of about 30 mesh through a swing granulator
  • Step 3 Dry the pellets in step 2 in a fluidized bed under the conditions that the material temperature is 40°C and the drying time is controlled at 50 minutes;
  • Step 4 Sieve the dried pellets obtained in step 3 to obtain pellet cores with particles of 30-60 mesh size;
  • Step 5 Preparation of the hot-melt coating material: the coating layer includes a low-melting point lipid material and an inert material, accounting for 85% and 15% by mass respectively; wherein, the low-melting point lipid material is glyceryl stearate; The inert material is calcium carbonate.
  • Step 6 Mix the pellet core particles obtained in step 4 with the hot-melt coating material obtained in step 5 according to a mass ratio of 10:1 and place them evenly in a closed fluidized bed, turn on the fluidized bed to heat and induce air, Set the inlet air temperature to 65°C. When the inlet air temperature gradually rises to or above the melting point of the low-melting lipid material, the lipid material begins to dissolve; when the temperature of the material reaches 65°C, continue heating for 35 minutes to ensure The low melting point lipid material melts completely.
  • Step 7 Turn off the heating, keep the induced draft and continue to open, and the temperature in the fluidized bed will slowly cool down.
  • the temperature in the fluidized bed is lower than the melting point of the low-melting point lipid material, the low-melting point lipid material begins to solidify, and in the enzyme A tight hydrophobic layer is formed on the surface of the pellet core of the preparation, and a hot-melt coated high-yield glucose oxidase product is obtained.
  • the steps 1-4 of the traditional coating process are the same as the steps 1-4 of the hot melt coating method of the present invention in this embodiment;
  • Step 5 Weigh 20g of NE30D (ethyl acrylate-methyl methacrylate copolymer) dispersion, add a solvent to dilute to an appropriate concentration, mix well, and use it as a coating solution for later use.
  • NE30D ethyl acrylate-methyl methacrylate copolymer
  • Step 6 The air inlet temperature of the fluidized bed is 55°C, the outlet air temperature is 30°C, a spray gun is required, and the pressure of the spray gun is 0.4Mpa, and a peristaltic pump is added.
  • the parameter of the peristaltic pump is 140rpm/min, and the atomizer needs to be turned on. Spray the coating solution prepared in step 5.
  • the steps 1-5 of the traditional hot-melt coating process are the same as the steps 1-5 of the hot-melt coating method of the present invention in this embodiment;
  • step 6 the inlet air temperature of the fluidized bed is 120°C, the outlet air temperature is 40°C, a spray gun is required, the pressure of the spray gun is 0.3Mpa, and a peristaltic pump is added, and the parameter of the peristaltic pump is 140rpm/min.
  • the hot-melt material in the molten state is evenly sprayed on the surface of the material through an atomizer with heat preservation measures.
  • the reaction conditions need to be strictly controlled, otherwise it is easy to block the nozzle, and at the same time, high-temperature operation safety hazards should be avoided at all times.
  • Enzyme activity retention rate enzyme activity after treatment (U/g)/enzyme activity before treatment (U/g)*100%.
  • Embedding rate [(sample enzyme activity-filtrate enzyme activity)/sample enzyme activity] ⁇ 100%.
  • This embodiment takes high-yield glucose oxidase as the research object, adopts 3 different post-treatment processes (each process carries out 6 batches of tests) to carry out coating treatment to it, and the coating type enzyme preparation of preparation is carried out effect evaluation, the result As shown in Table 1. It can be seen from Table 1 that the heat-resistant retention rate, embedding rate, and granulation retention rate of the enzyme preparation after coating are all improved. However, compared with the traditional coating process and the traditional hot-melt coating process, this The enzyme preparation prepared by the invented hot-melt coating process increased by 152% and 92% after heat-resistant treatment, the encapsulation rate increased by 115% and 62%, and the granulation retention rate increased by 200% and 150% respectively.
  • the coating time is shortened to two-thirds and one-fifth of the traditional coating process and the traditional hot-melt coating process respectively. It can be seen from the data that the hot melt coating process of the present invention has better batch-to-batch repeatability and stability.
  • Embodiment 2 the preparation of coated granule ordinary glucose oxidase
  • a coated granular common glucose oxidase of the present invention is prepared by the following method:
  • Step 1 Mix the enzyme powder preparation, starch, sodium bicarbonate, monoglyceride, and water evenly to prepare a soft material.
  • mass percentage of each component 18% of enzyme preparation, 35% of starch, 15% of sodium glutamate, 1.5% of monoglyceride, 30.5% of water;
  • Step 2 Make the prepared soft material into pellets with a size of about 30 mesh through a swing granulator
  • Step 3 Dry the pellet flow in step 2 in the chemical bed, the condition is that the material temperature is 42°C, and the drying time is controlled at 45 minutes;
  • Step 4 Sieve the dried pellets obtained in step 3 to obtain pellet cores with particles of 30-60 mesh size;
  • Step 5 Preparation of hot-melt coating material: the coating layer includes low-melting point lipid material and inert material, accounting for 90% and 10% by mass respectively; wherein, the low-melting point lipid material is stearic acid and hydrogenated oil , the mass ratio is 1:1; the inert material is calcium sulfate and talcum powder, and the mass ratio is 1:1.
  • Step 6 Mix the pellet core particles obtained in step 4 with the hot-melt coating material obtained in step 5 in a mass ratio of 10:1 and place them evenly in a closed fluidized bed, turn on the fluidized bed to heat and induce air, Set the inlet air temperature to 65°C. When the inlet air temperature gradually rises to the melting point of the low melting point lipid material or higher, the lipid material begins to dissolve; when the temperature of the material reaches 65°C, continue heating for 30 minutes to ensure The low melting point lipid material melts completely.
  • Step 7 Turn off the heating, keep the induced draft and continue to open, and the temperature in the fluidized bed will slowly cool down.
  • the temperature in the fluidized bed is lower than the melting point of the low-melting point lipid material, the low-melting point lipid material begins to solidify, and in the enzyme A tight hydrophobic layer is formed on the surface of the pellet core of the preparation to obtain a hot-melt coated enzyme preparation product.
  • the glucose oxidase granules coated with hot melt and the uncoated glucose oxidase were subjected to heat resistance treatment evaluation (the specific method was the same as that in Example 1), and the retention rates were calculated respectively.
  • the specific results are shown in Table 2 below.
  • the glucose oxidase granules prepared after the coating process of the present invention can significantly improve the heat-resistant stability of glucose oxidase.
  • Embodiment 3 a kind of preparation method of coating type neutral protease
  • Step 1 Mix the enzyme powder preparation, starch, sodium bicarbonate, monoglyceride, and water evenly to prepare a soft material. Wherein the mass percentage of each component: 19% of enzyme preparation, 39% of starch, 17% of sodium glutamate, 1.8% of monoglyceride, 23.2% of water;
  • Step 2 Make the prepared soft material into pellets with a size of about 30 mesh through a swing granulator
  • Step 3 Dry the pellets in step 2 in a fluidized bed, the condition is that the material temperature is 40°C, and the drying time is controlled at 40 minutes;
  • Step 4 Sieve the dried pellets obtained in step 3 to obtain pellet cores with particles of 30-60 mesh size;
  • Step 5 Preparation of hot-melt coating material: the coating layer includes low-melting point lipid material and inert material, accounting for 90% and 10% by mass respectively; wherein, the low-melting point lipid material is glyceryl stearate; The inert material is kaolin.
  • Step 6 Mix the pellet core particles obtained in step 4 with the hot-melt coating material obtained in step 5 in a mass ratio of 10:1 and place them in a closed fluidized bed, turn on the fluidized bed to heat and induce air, Set the inlet air temperature to 65°C. When the inlet air temperature gradually rises to or above the melting point of the low-melting lipid material, the lipid material begins to dissolve; when the temperature of the material reaches 65°C, continue heating for 35 minutes to ensure The low melting point lipid material melts completely.
  • Step 7 Turn off the heating, keep the induced draft to continue to open, and the temperature in the fluidized bed is slowly cooled down.
  • the temperature in the fluidized bed is lower than the melting point of the low-melting point lipid material, the low-melting point lipid material begins to solidify, and the enzyme A tight hydrophobic layer is formed on the surface of the pellet core of the preparation to obtain a hot-melt coated enzyme preparation product.
  • the coated neutral protease granules and the uncoated neutral protease granules are subjected to heat-resistant treatment, and the retention rate is calculated respectively.
  • the specific results are shown in Table 3 below.
  • Embodiment 4 preparation of different weight-gaining enzyme preparations (phytase) coated granules
  • Step 1 Mix the enzyme powder preparation, starch, sodium bicarbonate, monoglyceride, and water evenly to prepare a soft material.
  • mass percentage of each component 20% of enzyme preparation, 40% of starch, 18% of sodium glutamate, 2% of monoglyceride, 20% of water;
  • Step 2 Make the prepared soft material into pellets with a size of about 30 mesh through a swing granulator
  • Step 3 Dry the pellets in step 2 in a fluidized bed under the conditions that the material temperature is 45°C and the drying time is controlled at 40 minutes;
  • Step 4 Sieve the dried pellets obtained in step 3 to obtain pellet cores with particles of 30-60 mesh size;
  • Step 5 Preparation of the hot-melt coating material: the coating layer includes a low-melting point lipid material and an inert material, and the mass ratios are 80% and 20% respectively; wherein, the low-melting point lipid material is glyceryl stearate and Paraffin wax, the mass ratio is 4:1; the inert material is calcium carbonate and kaolin, the mass ratio is 3:1.
  • the low-melting point lipid material is glyceryl stearate and Paraffin wax, the mass ratio is 4:1;
  • the inert material is calcium carbonate and kaolin, the mass ratio is 3:1.
  • Step 6 The pellet core particles obtained in step 4 and the hot-melt coating material obtained in step 5 are respectively according to the mass ratio of 10:0.6, 10:0.8, 10:1, 10:1.2 (the weight gain is 6% respectively , 8%, 10%, 12% (the coating material accounts for the weight of the ball core)) mix evenly and place in a closed fluidized bed, turn on the fluidized bed to heat and introduce air, and set the inlet air temperature to 65°C.
  • the wind temperature gradually rises to the melting point of the low-melting point lipid material or higher, the lipid material begins to dissolve; when the temperature of the material reaches 65°C, continue heating for 30 minutes to ensure that the low-melting point lipid material is completely melted.
  • Step 7 Turn off the heating, keep the induced draft and continue to open, and the temperature in the fluidized bed will slowly cool down.
  • the temperature in the fluidized bed is lower than the melting point of the low-melting point lipid material, the low-melting point lipid material begins to solidify, and in the enzyme A tight hydrophobic layer is formed on the surface of the pellet core of the preparation to obtain a hot-melt coated enzyme preparation product.

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Abstract

本发明涉及一种颗粒型酶制剂的热熔包被方法及其应用。该方法通过将含酶的微丸丸芯与由低熔点脂质材料和惰性材料组成的包被材料，按照质量比100:(8-10)均匀混合置于可通过热风加热内容物并可稳定控温的密闭设备，同时缓慢升温，体系温度达到65-70℃后停止升温，维持30-40min后缓慢冷却，随着温度下降，包被材料冷却后在颗粒表面形成一层均匀的包被层，得到密闭性好，酶活存留率高，对设备要求低(无需喷枪、雾化器)，简单易于操作且安全性高的热熔包被方法。

Description

一种颗粒型酶制剂的热熔包被方法及其应用 技术领域
本发明涉及酶制剂加工领域，具体涉及一种颗粒型酶制剂的热熔包被方法及其应用
背景技术
酶是一种生物催化剂，与其他蛋白质一样对温度、湿度、金属离子等因素比较敏感。饲用酶制剂大多以液态发酵生产，发酵菌株经发酵后得到发酵液，发酵液经不同的后处理工艺可得到不同剂型的酶制剂产品，有液体酶、粉酶、普通颗粒酶和包被型颗粒酶，其中，包被型颗粒酶的稳定性最好，因为其表面有一层坚固而易溶的薄膜包衣，使酶颗粒与外界隔离，更利于酶的稳定。在颗粒饲料加工多采用制粒和膨化工序，因其在高温、高湿条件下进行，对酶活性会造成很大影响。
目前，为了让酶制剂在实际生产中最大限度的发挥催化作用，主要从两个方面进行研究，一方面是通过自然选择法、基因工程等手段开发新的发酵生产菌种，以提高其在制粒和膨化过程酶活的存留率，但一般难度较大。另一方面是通过选择合适的后处理工艺，主要包括在处理发酵酶液时添加稳定剂、选择合适的载体材料以及对酶进行包被处理。适当的稳定剂的种类和浓度，包被原料的选择以及筛选合适的包衣材料和包被工艺很关键。既要求其耐高温、高湿，而且在消化道能迅速释放被胃肠道利用,同时要求酶活存留率高，耗时短，加工成本低。
热熔包被(热融包衣)是指将包被材料以熔融状态覆盖于底物表面然后冷却固化形成衣膜从而阻断高温高湿对底物的影响。热熔包被的过程与传统包被技术不同，它没有使用溶剂。但传统的热熔包被工艺需要将包被材料预先融化，通过喷涂装置覆盖于底物表面，因此为了形成高质量的衣膜须在包衣过程保持物料温度接近于包衣液的凝固点，在这个过程中，为了保持包衣液流动性和可喷雾性，就需要使用蒸汽套和加热带等装置保持包衣液的温度，对仪器设备要求较高。包被材料在输送过程中受温度影响较敏感，容易出现堵塞喷嘴的现象，导致传统工 艺既耗能又不便操作。同时，传统热熔包被要求包衣材料的熔点低于85℃，并在150℃左右有稳定的理化性质，因为包衣材料的喷雾需保持在高于熔点约60℃的温度下进行，对于酶制剂来说，温度较高会使酶制剂失活严重。张娜等(“热熔包衣及数对丹参颗粒吸湿性的影响研究”，中成药，2013,35(1),187～189)公开了一种热熔包衣方法，需密切注意进风温度和流化状态，当在流化的底物中发现白色粉末，应适当提高进风温度。此方法对操作者要求较高且耗时较长。CN109966265A的专利文献中公开了一种伪麻黄碱缓释小丸包衣方法。此方法对生产仪器包衣机要求严格，必须是带有蒸汽套和加热带等保温装置的流化床包衣机，生产成本高。另一方面加热后的包被材料与热空气存在安全隐患，实际操作中容易烫伤。
发明内容
本发明针对现有技术的不足，开发出一种适用于酶制剂的热熔包被方法。
本发明中的热熔包被方法包括将含酶的微丸丸芯与由低熔点脂质材料和惰性材料组成包被材料按照质量比100:(8-10)均匀混合置于可通过热风加热内容物并可稳定控温的密闭设备内，加热、引风，体系温度达到65-70℃后维持30-40min，然后缓慢冷却。所述可稳定控温的密闭设备优选为流化床或沸腾床。
具体的，所述方法包括：
步骤1：将酶粉状制剂、淀粉、元明粉、单甘脂、水混合均匀制备软材。其中各组分质量百分比：酶制剂16％-20％，淀粉35％-40％，元明粉13％-18％，单甘脂0.5％-2％，水20％-35％；优选的，各组分质量百分比：酶制剂16％，淀粉37％，元明粉18％，单甘脂2％，水27％。
步骤2：将制备好的软材通过摇摆制粒机制成微丸。
步骤3：将步骤2中的微丸烘干得到微丸丸芯，条件为物料温度40-45℃，烘干时间控制在40-60min；优选的，所述烘干在流化床内进行。
优选的，将步骤3得到30-60目大小颗粒的微丸丸芯；
步骤4：热熔包被材料的制备：热熔包被材料包括低熔点脂质材料和惰性材料，所占质量比分别为80％-90％和10％-20％；其中，低熔点脂质材料的熔点≤65℃，优选的，低熔点脂质材料为硬脂酸甘油酯、硬脂酸、氢化油、石蜡的任意一种或两种以上任意比例的混合物；惰性材料为碳酸钙、硫酸钙、滑石粉、高岭 土的任意一种或两种以上任意比例的混合物。
步骤5：将步骤3中得到的微丸丸芯与步骤4中得到的热熔包被材料按质量比100:(8-10)混合均匀置于密闭设备内，开启加热、引风，将进风温度设置成65-70℃，当物料的温度达到65-70℃时，继续加热30-40min，确保低熔点脂质材料全部熔化；
步骤6：关闭加热，保持引风继续开启，密闭设备内温度慢慢冷却下来，当温度低于低熔点脂质材料的熔点时，低熔点脂质材料开始凝固，并在酶制剂丸芯表面形成一层紧密的疏水层，得到热熔包被型酶制剂产品。
本发明还提供一种采用前述酶制剂的热熔包被方法制备的酶制剂。
本发明还提供一种前述酶制剂的热熔包被方法在饲用酶制剂领域的应用，其中，饲用酶制剂包括但不限于植酸酶、葡萄糖氧化酶、蛋白酶等饲用酶制剂。
本发明将包被材料与颗粒丸芯同时置于密闭设备，同时升温，包被时间缩短到传统热熔包被工艺的五分之一，并且此方法条件温和，重复性高，通过该方法包被的酶制剂颗粒包被密闭性好，对设备要求低(无需喷枪、雾化器等设备)，加热后的包被材料与热空气间不存在安全隐患，实际操作中不易烫伤，操作步骤简便；可以显著提高包被后的酶活存留率，且经过热熔包被的酶制剂耐热性能(耐热处理后酶活存留率)提升至原来的十倍以上。
具体实施方式
下面结合实施例对本发明进行进一步说明和描述，但所描述的实施例仅仅是本发明的一部分实施例，而不是全部的实施例。基于本发明和实施例中，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他发明和实施例，都属于本发明保护的范围。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1、不同包被工艺对饲用高产葡萄糖氧化酶制剂包被效果的比较研究1、包被工艺步骤：
1)本发明热熔包被方法技术参数：
步骤1：将酶粉状制剂、淀粉、元明粉、单甘脂、水混合均匀制备软材。其中各组分质量百分比：酶制剂16％，淀粉37％，元明粉18％，单甘脂2％，水27％；
步骤2：将制备好的软材通过摇摆制粒机制成大小约30目的微丸；
步骤3：将步骤2中的微丸在流化床内进行烘干，条件为物料温度40℃，烘干时间控制在50min；
步骤4：将步骤3得到的烘干微丸进行筛分，得到30-60目大小颗粒的微丸丸芯；
步骤5：热熔包被材料的制备：包被层包括低熔点脂质材料和惰性材料，所占质量比分别为85％和15％；其中，低熔点脂质材料为硬脂酸甘油酯；惰性材料为碳酸钙。
步骤6：将步骤4中得到的微丸丸芯颗粒与步骤5中得到的热熔包被材料按质量比10:1混合均匀置于密闭的流化床内，开启流化床加热、引风，将进风温度设置成65℃，当进风温度逐渐升高至低熔点脂质材料的熔点或高于熔点时，脂质材料开始溶解；当物料的温度达到65℃时，继续加热35min，确保低熔点脂质材料全部熔化。
步骤7：关闭加热，保持引风继续开启，流化床内温度慢慢冷却下来，当流化床内温度低于低熔点脂质材料的熔点时，低熔点脂质材料开始凝固，并在酶制剂丸芯表面形成一层紧密的疏水层，得到热熔包被型高产葡萄糖氧化酶产品。
2)传统包被工艺方法技术参数：
传统包被工艺方法的步骤1-4与本实施例中本发明热熔包被方法的步骤1-4相同；
步骤5：称取20g NE30D(丙烯酸乙酯-甲基丙烯酸甲酯共聚物)分散体，加入溶剂稀释至适宜浓度，混合均匀，作为包衣液，待用。
步骤6：流化床进风温度55℃，出风温度30℃，需用喷枪，且喷枪压力0.4Mpa，增加蠕动泵，蠕动泵参数为140rpm/min，需要开启雾化器。喷入步骤5中配制好的包衣液。(参照蔡翠芳等，“对乙酰氨基酚包衣缓释微丸的制备和体外释放研究”，《中国药剂学杂志》，2003，第1卷第2期，p40-44)
3)传统热熔包被工艺方法技术参数：
传统热熔包被工艺方法的步骤1-5与本实施例中本发明热熔包被方法的步骤1-5相同；
步骤6中，流化床进风温度120℃，出风温度40℃，需用喷枪，喷枪压力 0.3Mpa，增加蠕动泵，蠕动泵参数140rpm/min。
熔融状态下的热熔材料通过具备保温措施的雾化器均匀地喷涂在物料表面，需严格控制反应条件，否则容易堵喷头，同时应时刻避免高温操作安全隐患。
2、不同工艺制备的颗粒型酶制剂的具体评估方法：
1)酶制剂颗粒的耐热处理方法：
称取1.00g待测样品置于铝盒内，平铺均匀，将铝盒放置在筛网上，锅中水加热至沸腾，将装有铝盒的筛网置于沸腾的水浴中，水面高度低于晒网高度，盖好锅盖，热蒸汽处理样品60秒，分别测定处理前后的酶活力，计算酶活存留率。
酶活存留率＝处理后酶活力(U/g)/处理前酶活力(U/g)*100％。
2)包被工艺后包埋率的评价方法：
准确称取1.000g样品平铺于布氏漏斗(ф10cm),在抽滤的同时用100mL的水洗涤样品，收集洗涤滤液，测定洗涤滤液酶活。
包埋率＝[(样品酶活-滤液酶活)/样品酶活]×100％。
3)包被酶制剂制粒留存率的评价方法：
用豆粕逐级稀释酶制剂样品，充分混合均匀后加入配合饲料，其中配合饲料按照常规配方配制。分别均匀采集制粒前，以及制粒后的样品各5-10份，每份100g左右，检测制粒前酶活(X1)和制粒后酶活(X2)。
酶活力存留率(％)＝(X2÷X1)×100％
本实施例以高产葡萄糖氧化酶为研究对象，采用3中不同的后处理工艺(每种工艺进行6批试验)对其进行包被处理，并将制备的包被型酶制剂进行效果评估，结果如表1所示。从表1中可以看出，包被后酶制剂的耐热存留率、包埋率、制粒留存率均有所提升，但是，与传统包被工艺和传统热熔包被工艺相比，本发明热熔包被工艺制备的酶制剂耐热处理后酶活存留率分别增加了152％和92％，包埋率分别提高了115％和62％，制粒留存率分别提高了200％和150％，同时，包被时间分别缩短至传统包被工艺和传统热熔包被工艺的三分之二和五分之一。由数据可以看出，本发明的热熔包被工艺批间重复性和稳定性更好。
表1
Figure PCTCN2022129636-appb-000001
Figure PCTCN2022129636-appb-000002
实施例2、包被型颗粒普通葡萄糖氧化酶的制备
本发明一种包被型颗粒普通葡萄糖氧化酶，通过以下方法制备：
步骤1：将酶粉状制剂、淀粉、元明粉、单甘脂、水混合均匀制备软材。其中各组分质量百分比：酶制剂18％，淀粉35％，元明粉15％，单甘脂1.5％，水30.5％；
步骤2：将制备好的软材通过摇摆制粒机制成大小约30目的微丸；
步骤3：将步骤2中的微丸流在化床内进行烘干，条件为物料温度42℃，烘干时间控制在45min；
步骤4：将步骤3得到的烘干微丸进行筛分，得到30-60目大小颗粒的微丸丸芯；
步骤5：热熔包被材料的制备：包被层包括低熔点脂质材料和惰性材料，所占质量比分别为90％和10％；其中，低熔点脂质材料为硬脂酸和氢化油，质量比为1:1；惰性材料为硫酸钙和滑石粉，质量比为1:1。
步骤6：将步骤4中得到的微丸丸芯颗粒与步骤5中得到的热熔包被材料按质量比10：1混合均匀置于密闭的流化床内，开启流化床加热、引风，将进风温度设置成65℃，当进风温度逐渐升高至低熔点脂质材料的熔点或高于熔点时，脂质材料开始溶解；当物料的温度达到65℃时，继续加热30min，确保低熔点脂质材料全部熔化。
步骤7：关闭加热，保持引风继续开启，流化床内温度慢慢冷却下来，当流化床内温度低于低熔点脂质材料的熔点时，低熔点脂质材料开始凝固，并在酶制 剂丸芯表面形成一层紧密的疏水层，得到热熔包被型酶制剂产品。
将热熔包被葡萄糖氧化酶颗粒与未包被的葡萄糖氧化酶进行耐热处理评估(具体方法同实施例1中)，分别计算存留率。具体结果见下表2。
表2
Figure PCTCN2022129636-appb-000003
由上表2数据可知，经过本发明的包被工艺后制备的葡萄糖氧化酶颗粒能够显著提高葡萄糖氧化酶的耐热稳定性。
实施例3、一种包被型中性蛋白酶的制备方法
通过以下方法制备：
步骤1：将酶粉状制剂、淀粉、元明粉、单甘脂、水混合均匀制备软材。其中各组分质量百分比：酶制剂19％，淀粉39％，元明粉17％，单甘脂1.8％，水23.2％；
步骤2：将制备好的软材通过摇摆制粒机制成大小约30目的微丸；
步骤3：将步骤2中的微丸流化床内进行烘干，条件为物料温度40℃，烘干时间控制在40min；
步骤4：将步骤3得到的烘干微丸进行筛分，得到30-60目大小颗粒的微丸丸芯；
步骤5：热熔包被材料的制备：包被层包括低熔点脂质材料和惰性材料，所占质量比分别为90％和10％；其中，低熔点脂质材料为硬脂酸甘油酯；惰性材料为高岭土。
步骤6：将步骤4中得到的微丸丸芯颗粒与步骤5中得到的热熔包被材料按质量比10:1混合均匀置于密闭的流化床内，开启流化床加热、引风，将进风温度设置成65℃，当进风温度逐渐升高至低熔点脂质材料的熔点或高于熔点时，脂质材料开始溶解；当物料的温度达到65℃时，继续加热35min，确保低熔点脂质材料全部熔化。
步骤7：关闭加热，保持引风继续开启，流化床内温度慢慢冷却下来，当流化床内温度低于低熔点脂质材料的熔点时，低熔点脂质材料开始凝固，并在酶制剂丸芯表面形成一层紧密的疏水层，得到热熔包被型酶制剂产品。
将包被好的中性蛋白酶颗粒与未包被的中性蛋白酶颗粒进行耐热处理，分别计算存留率。具体结果见下表3。
表3
Figure PCTCN2022129636-appb-000004
由上表3数据可知，经过包被工艺制备的植酸酶颗粒显著提高了中性蛋白酶的耐热存留率。
实施例4、不同增重酶制剂(植酸酶)包被颗粒的制备
1)包被型颗粒植酸酶，通过以下方法制备：
步骤1：将酶粉状制剂、淀粉、元明粉、单甘脂、水混合均匀制备软材。其中各组分质量百分比：酶制剂20％，淀粉40％，元明粉18％，单甘脂2％，水20％；
步骤2：将制备好的软材通过摇摆制粒机制成大小约30目的微丸；
步骤3：将步骤2中的微丸在流化床内进行烘干，条件为物料温度45℃，烘干时间控制在40min；
步骤4：将步骤3得到的烘干微丸进行筛分，得到30-60目大小颗粒的微丸丸芯；
步骤5：热熔包被材料的制备：包被层包括低熔点脂质材料和惰性材料，所占质量比分别为80％和20％；其中，低熔点脂质材料为硬脂酸甘油酯和石蜡，质量比4:1；惰性材料为碳酸钙和高岭土，质量比为3:1。
步骤6：将步骤4中得到的微丸丸芯颗粒与步骤5中得到的热熔包被材料分别按照质量比10:0.6，10:0.8,10:1,10:1.2(增重分别为6％，8％，10％，12％(包被材料占丸芯重量))混合均匀置于密闭的流化床内，开启流化床加热、引风，将进风温度设置成65℃，当进风温度逐渐升高至低熔点脂质材料的熔点或高于熔点时，脂质材料开始溶解；当物料的温度达到65℃时，继续加热30min，确保低熔点脂质材料全部熔化。
步骤7：关闭加热，保持引风继续开启，流化床内温度慢慢冷却下来，当流化床内温度低于低熔点脂质材料的熔点时，低熔点脂质材料开始凝固，并在酶制剂丸芯表面形成一层紧密的疏水层，得到热熔包被型酶制剂产品。
表4不同增重的酶制剂包被颗粒对耐热效果的影响
Figure PCTCN2022129636-appb-000005
Figure PCTCN2022129636-appb-000006
由表4中数据可知，包被后的植酸酶颗粒经过耐热处理的酶活存留率与增重量呈正相关，增重量越大形成的疏水层越厚，颗粒均匀度越高。但是，在包被颗粒的制备过程中，随着温度的下降，当增重为12％时，由于过高添加量的低熔点脂质材料在形成疏水层时容易粘结在一起，造成颗粒成团，流散性下降，导致无法正常使用。所以应控制增重在8-10％。

Claims (9)

  1. 一种颗粒型酶制剂的热熔包被方法，其特征在于，所述包被方法包括将含酶的微丸丸芯与由低熔点脂质材料和惰性材料组成的包被材料，按照质量比100:(8-10)均匀混合置于可通过热风加热内容物并可稳定控温的密闭设备内，加热、引风，体系温度达到65-70℃后维持30-40min，然后缓慢冷却。
  2. 根据权利要求1所述的热熔包被方法，其特征在于，所述可稳定控温的密闭设备为流化床或沸腾床。
  3. 根据权利要求1或2所述的热熔包被方法，其特征在于，包括步骤如下：
    步骤1：将酶粉状制剂、淀粉、元明粉、单甘脂、水混合均匀制备软材；
    步骤2：将制备好的软材通过摇摆制粒机制成微丸；
    步骤3：将步骤2中的微丸烘干得到微丸丸芯，烘干条件为物料温度40-45℃，烘干时间控制在40-60min；
    步骤4：热熔包被材料的制备：热熔包被材料包括低熔点脂质材料和惰性材料，所占质量比分别为80％-90％和10％-20％，其中所述低熔点脂质材料的熔点≤65℃；
    步骤5：将步骤3中得到的微丸丸芯与步骤4中得到的热熔包被材料按质量比100:(8-10)混合均匀置于密闭设备内，开启加热、引风，将进风温度设置成65-70℃，当物料的温度达到65-70℃时，继续加热30-40min，确保低熔点脂质材料全部熔化；
    步骤6：关闭加热，保持引风继续开启，密闭设备内温度慢慢冷却下来，当温度低于低熔点脂质材料的熔点时，低熔点脂质材料开始凝固，并在酶制剂丸芯表面形成一层紧密的疏水层，得到热熔包被型酶制剂产品。
  4. 根据权利要求3所述的热熔包被方法，其特征在于，所述步骤1中各组分质量百分比：酶制剂16％-20％，淀粉35％-40％，元明粉13％-18％，单甘脂0.5％-2％，水20％-35％。
  5. 根据权利要求3所述的热熔包被方法，其特征在于，所述低熔点脂质材料为硬脂酸甘油酯、硬脂酸、氢化油、石蜡的任意一种或两种以上任意比例的混合物；和/或惰性材料为碳酸钙、硫酸钙、滑石粉、高岭土的任意一种或两种以 上任意比例的混合物。
  6. 根据权利要求3所述的热熔包被方法，其特征在于，所述步骤3还包括将得到的烘干微丸进行筛分，得到30-60目大小颗粒的微丸丸芯。
  7. 一种颗粒型酶制剂，其特征在于，采用权利要求1-6任一项所述的热熔包被方法制备而成。
  8. 一种权利要求1-6任一项所述的颗粒型酶制剂的热熔包被方法在饲用酶制剂领域的应用。
  9. 根据权利要求8所述的应用，其特征在于，所述饲用酶制剂包括植酸酶、葡萄糖氧化酶和蛋白酶。
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