CN107669657B - Preparation method of high-stability microcapsule containing double-bond fat-soluble nutrient - Google Patents
Preparation method of high-stability microcapsule containing double-bond fat-soluble nutrient Download PDFInfo
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- 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
- A61K9/5057—Gelatin
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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
- A61K31/045—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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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- 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
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- 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
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- 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
- A61K9/5123—Organic compounds, e.g. fats, sugars
Abstract
The invention provides a preparation method of high-stability microcapsule containing double-bond fat-soluble nutrient, which comprises the steps of firstly mixing and dissolving a small amount of emulsion stabilizer and water to obtain a water phase, dissolving the fat-soluble nutrient in an oil phase formed by an organic solvent, emulsifying and mixing, then homogenizing under high pressure to obtain a nano-scale oil-in-water type emulsion, removing the organic solvent in the emulsion, directly adding a coating wall material into the emulsion, shearing and mixing uniformly under mild conditions, and obtaining microcapsule dry powder or particles after granulation and drying. The microcapsule dry powder and the microcapsule particles obtained by the preparation method have good stability and no bad smell, and are suitable for being applied to food and dietary supplements.
Description
Technical Field
The invention relates to a preparation method of microcapsule dry powder/particles with high stability of fat-soluble nutrients. More specifically, the invention creatively dissolves the nutrients in an organic solvent, and the nutrients and the water phase in which only a small amount of emulsion stabilizer is dissolved are emulsified and mixed through high shear to obtain nano-dispersed emulsion, then the organic solvent is immediately removed, nano-scale particles formed by the stability of an embedding wall material are added, and after granulation and drying, the high-stability microcapsule dry powder or particles are obtained. In the process, the damage effect of the organic solvent on the embedding wall material is avoided, and the stability of the product is enhanced.
Background
With health concerns, more people are increasingly willing to maintain health by daily intake of certain vitamins and healthy dietary ingredients, among which fat-soluble vitamins such as VA, VE, VD3 and others such as omega-3, omega-6, omega-9 fatty acids in polyunsaturated fatty acids, beta-carotene in carotenoids, lutein, zeaxanthin, astaxanthin, lycopene, curcumin, retinoids such as coenzyme Q10, reduced coenzyme Q10, etc. are more widely used varieties.
The nutrients have health functions mainly due to the existence of more double bonds in the molecular structural formula, the double bonds can better eliminate free radicals in the body in human bodies and resist oxidation, the free radicals are one of important causes of aging and various diseases, and it is estimated that about 80-90% of aging and degenerative diseases are related to the free radicals, wherein the aging and degenerative diseases comprise cancers, senile dementia, Parkinson's disease, skin dark spot deposition, cataract, heart disease and the like. The elimination of harmful free radicals is essential to maintaining the health and youth of the body.
The structural formulae and the efficacies of several nutrients are as follows:
vitamin A
Vitamin a is an important member of the fat-soluble vitamin family, which has very important functions in terms of visual health, bone health, reproduction and cell division, and the lack of vitamin a in the human body is not imaginable. The major forms of vitamin A are vitamin A alcohol, vitamin A acetate and vitamin A palmitate.
Vitamin E
Vitamin E, which includes both natural and synthetic sources, is a well-known antioxidant. Vitamin E exists in 8 forms, namely four monomers of alpha, beta, gamma and delta, each monomer has two optical isomers, and the alpha-form is mainly applied to the market and comprises free tocopherol, tocopherol acetate, tocopherol succinate, tocopherol nicotinate and the like.
Polyunsaturated fatty acids
Polyunsaturated fatty acids have irreplaceable functions in the human body, the main functions of which are mainly reflected in: the relative fluidity of the cell membrane is maintained to ensure the normal physiological function of the cell. Esterify cholesterol, reduce cholesterol and triglyceride in blood. Reduce blood viscosity and improve blood microcirculation. Improving brain cell activity, and improving memory and thinking ability.
The polyunsaturated fatty acids mainly include two forms of omega-3 fatty acids and omega-6 fatty acids, the former includes alpha-Linolenic Acid (alpha-Linolenic Acid), Eicosapentaenoic Acid (EPA), Docosahexaenoic Acid (Docosahexaenoic Acid, DHA), docosapentaenoic Acid (DPA), etc., and the latter includes Linoleic Acid (Linoleic Acid, LA), Conjugated Linoleic Acid (CLA), gamma-Linolenic Acid (gamma-Linolenic Acid), Arachidonic Acid (Arachidonic Acid, AA). The molecular structural formula of these polyunsaturated fatty acids is as follows:
fish oil derived from deep sea fish such as anchovy, tuna, squid, etc. mainly contains polyunsaturated fatty acids such as EPA and DHA. Another source of DHA and EPA is artificially cultured algae.
Carotenoid
Carotenoids are synthesized by plants, exist in the natural world in the form of pigments, and over 600 kinds have been found so far, among which only beta-carotene, lycopene, astaxanthin, lutein, zeaxanthin, and the like are considered as the more important carotenoids. Some of these carotenoids can be converted into vitamin A in the human and animal body, and exert the physiological action of vitamin A. Therefore, it is called "provitamin A".
The main functions of carotenoids are: is one of the most effective antioxidants against free radicals; strengthening immune system and enhancing resistance; preventing and resisting cancer; reducing the chance of oral cancer, breast cancer, cervical cancer, lung cancer, trachea, esophagus, intestines and stomach and bladder cancer; preventing heart and blood vessel diseases; preventing cataract, and protecting fiber part of eye lens; strengthening urinary system and preventing prostatosis; the natural eye drop is used for improving bursitis of tendinitis caused by rheumatic arthritis, helps to keep the lubrication and transparency of eye cornea and promotes eye health; precursors of VA, which can be converted to VA, help maintain the health of the skin and the mucosa of the organ's lumen, etc.
Curcumin (curcumin)
Curcumin is a promising nutrient which can inhibit oxidation and scavenge free radicals, has anti-inflammatory response, is anticoagulated, regulates lipid, resists lipid peroxidation, inhibits plaque formation, inhibits vascular smooth muscle cell proliferation and the like. The molecular structural formula is as follows:
coenzyme Q10
Coenzyme Q10 is a fat-soluble compound widely existing in organisms, widely distributed in nature, mainly exists in yeast, plant leaves, seeds and cells of heart, liver and kidney of animals, and is one of the most important coenzymes of human bodies. The main functions of coenzyme Q10 are: scavenging free radicals, resisting tumor, enhancing immunity, activating metabolism, and enhancing heart tolerance to anoxia.
It can be seen that these nutrients have at least two common characteristics, that is 1) are both lipid soluble, but have very low solubility in vegetable oils; 2) many double bonds are present in the molecular structure.
Because of their fat solubility, they have greatly limited their range and mode of application, either in oil-based foods or by being administered in soft gelatin capsules, or by modifying their solubility to make them water-soluble, and thus can be used in water-based foods. An important way to change the solubility is to make these nutrients water soluble by microencapsulation.
The double bonds in large quantity, on one hand, endow the nutrients with good oxidation resistance, can scavenge free radicals in the body and thus embody the physiological functions of the nutrients, on the other hand, make the nutrients extremely unstable, not only in the storage process, but also in the processing process such as microencapsulation process, and are very easily degraded or reduced in bioactivity under the influence of heat and light in the processing process, and particularly under higher pressure, the degradation process caused by heat is more obvious.
Moreover, since many of these fat-soluble nutrients are fat-soluble but their solubility in fat is not great, in order to prepare a nano-scale stable nutrient microcapsule product, the nutrients should be completely dispersed in the coating colloid wall material during the preparation process. There are several methods for dispersing nutrients in the coating wall material, respectively, dissolving the nutrients in the vegetable oil, melting the nutrients at high temperature, grinding and dispersing the nutrients, and dissolving the nutrients in the organic solvent.
In the prior art, a number of methods have been developed for preparing these fat-soluble nutritional microcapsule products, for example US Patent 2007/0128341 discloses a method for preparing polyunsaturated fatty acids, in particular fish oil-derived polyunsaturated fatty acid microcapsule emulsions or dry powders using milk proteins, which simultaneously microencapsulate the milk proteins and the polyunsaturated fatty acids.
US Patent 2008/0254184 describes a formulation for the production of polyunsaturated fatty acid microcapsules using gum arabic, but the use of gum arabic is limited by the inclusion of wall materials.
CN 101177540B describes a process for preparing water-soluble carotenoid microcapsule dry powder, in which carotenoid is dissolved by organic solvent, and after mixing with water, the mixture is homogenized under high pressure at higher temperature and viscosity to obtain emulsion, the homogenization pressure used in the process is higher, in order to reduce the viscosity of the emulsion before homogenization, a large amount of water has to be added, and the water is concentrated before spray granulation, which causes waste of energy and operation.
CN 1022278257A relates to an algae oil DHA microcapsule process. In the process, the wall material modified starch and the Arabic gum are added step by step, an emulsifier, a water phase, an emulsified phase, a comprehensive phase and an emulsion are prepared in sequence, multiple mixing, shearing and homogenizing processes are involved, a large amount of water is added for achieving the homogenizing effect, particularly, extra steps are needed to degas and remove the extra water before spray drying, the process is complex and long, and the efficiency is low.
In summary, in the disclosed preparation process of the microcapsule aiming at unstable and fat-soluble nutrients containing more double bonds, some products obtained have poor stability and cannot meet the expected requirements; some processes are complex, involve a plurality of steps, the inefficiency; some of the methods have harsh operating conditions and are difficult to realize industrially. These methods have respective disadvantages, for example, because these nutrients have low solubility in oils and fats, and a large amount of vegetable oil is required for complete dissolution, which inevitably results in a nutrient microcapsule product having a low content of active ingredients. By the high-temperature melting method, the nutrients are degraded or isomerized at high temperature, and the biological activity of the nutrients is reduced. The particle size of the nutrient obtained by the grinding dispersion method is not sufficiently fine. The preparation method is a good microcapsule preparation method, but the conventional organic solvent method for preparing the microcapsule has several defects, namely, the organic solvent has a destructive effect on an embedding wall material, such as gelatin, and a plurality of organic solvents have a denaturation effect on the wall material, so that the coating performance of the microcapsule is reduced. Secondly, most of the coated wall materials have emulsifying performance, so that the organic solvent is difficult to remove due to the presence of the coated wall materials, so that the organic solvent of the final product is more remained, and certain risks are brought to the safety of the product. Finally, the viscosity of the emulsion is increased due to the existence of the coating wall material, so that the removal of the organic solvent is more difficult, the time for removing the organic solvent is prolonged, and the stability of the product is not good.
There is a need for a relatively general and simple method, which fully utilizes the advantages of small emulsion particle size, small oil phase volume, high content of effective components in the final product and the like when an organic solvent is used for preparing a fat-soluble nutrient microcapsule product, and simultaneously reduces the damage effect of the organic solvent on an embedding wall material as much as possible, and simultaneously removes the organic solvent in the final product as much as possible, thereby improving the safety of the final product.
In order to solve the problems, the invention creatively solves the problem that the coating wall material is added after the nano-scale emulsion droplets are formed and the organic solvent is completely removed. Dissolving fat-soluble nutrients in a small amount of organic solvent to form a uniform solution, mixing the uniform solution with a water phase dissolved with an emulsion stabilizer, emulsifying by high shear, homogenizing under high pressure to form a nano-scale emulsion, removing the organic solvent in the emulsion under reduced pressure, adding a dissolved coating wall material, emulsifying by high shear to obtain an oil-in-water emulsion, and spray granulating and drying to obtain a microcapsule dry powder or particle product. The obtained microcapsule product has good stability, strong pressure resistance, low organic solvent residue, and good applicability and safety.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention describes a preparation method of high-stability microcapsules containing more double-bond fat-soluble nutrients.
Specifically, a) dissolving fat-soluble nutrients containing more unsaturated double bonds in an organic solvent to prepare an oil phase; b) dissolving an emulsion stabilizer in water to prepare a water phase; c) shearing, mixing and emulsifying the water phase and the oil phase to obtain an emulsion; d) homogenizing the obtained emulsion by a high-pressure homogenizer to ensure that the average particle size of liquid drops in the emulsion reaches the nanometer level; e) recovering the organic solvent; f) directly adding the aqueous solution of the coating material or the coating wall material into the emulsion after the organic solvent is recovered, shearing, mixing and dissolving; and g) carrying out spray granulation and drying to obtain microcapsule dry powder or micro-particles with good stability.
In a preferred technical scheme of the invention, the amount of the organic solvent in the step a) is preferably enough to completely dissolve the fat-soluble nutrient, and the volume-to-mass ratio of the organic solvent to the fat-soluble organic solvent is preferably 1: 2-1: 30.
In a preferred technical scheme of the invention, preferably, the dissolving temperature of the fat-soluble nutrient in the organic solvent in the step a) is enough to enable the fat-soluble nutrient to be completely dissolved, and is preferably between 20 and 100 ℃.
In the preferable technical scheme of the invention, the ratio of the emulsion stabilizer to the water in the step b) is preferably 30-250 times.
In the preferable technical scheme of the invention, the temperature of the water phase prepared in the step b) is preferably between 30 and 80 ℃.
In the preferable technical scheme of the invention, the proportion of the water phase and the oil phase in the step c) is preferably in the range of 0.3-3.2.
In the preferable technical scheme of the invention, the high-pressure homogenizing pressure in the step d) is preferably 20-60 Mpa.
In a preferred technical scheme of the invention, when the aqueous solution of the coating wall material is added in the step f), the ratio of water to the coating wall material is preferably 0-2 times.
The "fat-soluble nutrient containing more double bonds" in the present invention refers to a substance having two or more double bonds in its molecular structural formula, being fat-soluble, and having a definite health function for human body, and includes, but is not limited to, vitamin a, vitamin E, natural vitamin E, vitamin D3, coenzyme Q10, curcumin, carotenoids, and polyunsaturated fatty acids. The carotenoid includes beta-carotene, lutein, astaxanthin, lycopene, zeaxanthin, etc.; the polyunsaturated fatty acid can be omega-3 polyunsaturated fatty acid derived from fish oil, omega-3 polyunsaturated fatty acid derived from fermentation, conjugated linoleic acid, arachidonic acid, etc. Because these nutrients contain a large number of double bonds, they are not particularly stable to light, oxygen and heat, and are easily affected by heating in the processing process, or may generate certain degradation products or polymers, or may isomerize, which may reduce the health efficacy of the final product, and may generate certain unpleasant odor in the product, affecting its use.
The "coating wall material" in the present invention refers to a substance capable of encapsulating nutrients therein to form microcapsules and isolating the effective nutrients from air, and includes, but is not limited to, animal materials such as gelatin, plant materials such as gum arabic, modified starch, sodium caseinate, etc. As people's sensitivity to materials of animal origin increases, gum arabic and modified starch of plant origin are preferred.
The "emulsion stabilizer" in the present invention refers to a conventional emulsifier such as ascorbyl palmitate, mono-and diglycerides, lecithin, sorbitol fatty acid ester, polyethylene glycol succinate, etc., but does not include a conventional coating stabilizer and wall material such as gelatin, modified starch, sodium caseinate, gum arabic, etc.
The "organic solvent" in the present invention refers to an organic solvent having a low boiling point, which is conventionally effective for dissolving fat-soluble nutrients, such as methylene chloride, ethyl acetate, isobutyl acetate, acetone, ethanol, butanone, tetrahydrofuran, isobutanol, isopropanol, and the like.
"nanoscale" in the present invention means that the average particle diameter of the liquid droplets is less than 1 μm after the microcapsule emulsion or microcapsule dry powder/microparticles are dispersed in water.
The term "high stability" in the present invention means that the microcapsule dry powder/fine particles have good stability per se and also have good stability after being compressed into tablets under high pressure. Evaluation can be performed by the following simple method.
And (3) packaging the microcapsule dry powder/particle simulated commodity, sealing and protecting from light, storing at 40 ℃, detecting the content after 0,1,2 and 3 months respectively, and detecting the content retention rate after 3 months to be more than 90%.
Directly tabletting the microcapsule dry powder/particles without adding auxiliary materials, simulating commodity packaging, sealing and keeping out of the sun, storing at 40 ℃, detecting the content after 0,1,2 and 3 months respectively, and detecting the content retention rate after 3 months to be more than 85%.
The bad smell of the microcapsule dry powder/particles can be quantitatively evaluated by an electronic nose way besides the nose smell:
the detection mode is as follows: a broad spectrum hand held Volatile Organic Compound (VOC) gas detector model MiniRAE 3000 was used.
A detection step: taking 10g of sample, putting the sample into a wide-mouth bottle, placing the wide-mouth bottle in a 60 ℃ water bath kettle, covering a bottle stopper, preserving heat for 10min, opening the stopper, placing a detector probe on the bottle mouth for detection, and recording the reading to describe the smell of the sample.
In the process of the present invention, water-soluble antioxidants such as vitamin C, ascorbyl palmitate, etc. may be added to the water phase, and oil-soluble antioxidants such as synthetic tocopherol, mixed tocopherol, ascorbyl palmitate, lecithin, rosemary, etc. may be added to the oil phase, as desired. These antioxidants contribute to the stability of the nutrients in the final product microcapsule dry powder or microparticles.
It is known that organic solvents have certain destructive effect on coating wall materials such as gelatin, Arabic gum, modified starch, casein and the like, particularly under the conditions of high temperature and long time, the destructive effect is stronger, the organic solvents can denature the structure of the coating wall to reduce the coating performance of the coating wall, and in severe cases, flocculation can be generated to make the generated emulsion extremely unstable, so that the stability of the final product microcapsule is also reduced.
In the conventional process for preparing fat-soluble nutrient microcapsule products, especially nutrients in a crystalline state such as carotenoid, a large amount of organic solvent is used for dissolving crystals before microencapsulation, the nutrients dissolved in the organic solvent are fully contacted with the coated wall material at high temperature in the high-speed shearing and emulsifying process of the nutrients and the water phase containing the coated wall material, and in the subsequent process of removing the organic solvent, the wall material is continuously influenced by the organic solvent for a long time, and the existence of the organic solvent inevitably changes the molecular structure of the coated wall material to a certain extent, so that the coating performance of the coated wall material is reduced. Particularly, the organic solvent containing oxygen atoms, such as tetrahydrofuran, has extremely obvious destructive effect on protein coating wall materials, such as gelatin and casein, and can completely denature the coating wall materials in serious cases, completely destroy the three-dimensional molecular structure and lose the coating performance.
Moreover, in the emulsification and mixing process of the water phase and the oil phase, the existence of the coating wall material inevitably increases the viscosity of the emulsion, thereby increasing the difficulty of obtaining nano-scale emulsion droplets in the emulsification process and reducing the stability of the nutrient microcapsule dry powder or particles of the final product.
In the present invention, the emulsion stabilizer is first dissolved in water to form an aqueous phase, and no coating wall material is added to the aqueous phase as in the conventional method. Dissolving fat-soluble nutrient in organic solvent to form oil phase. And fully mixing and emulsifying the water phase and the oil phase under the condition of high shear, and homogenizing to obtain the emulsion without the coating wall material. Removing the organic solvent in the emulsion under reduced pressure or normal pressure, immediately adding the coating wall material or the aqueous solution of the coating wall material, and simply shearing and stirring to enable the coating wall material to be better wrapped around the nutrient liquid drop to form the microcapsule liquid drop. And then the microcapsule dry powder/particle product of the fat-soluble nutrient is obtained by means of spray granulation, drying and the like. The microcapsule product has good stability, even after being compressed into tablets under high pressure, and no bad smell is generated in the storage process.
The coating wall material is not added before emulsification but added after the emulsification finishes the removal of the organic solvent, so that on one hand, the damage effect of the organic solvent on the molecular structure of the coating wall material in the emulsification homogenization and removal processes can be avoided, thereby keeping the good coating performance of the coating wall material, on the other hand, the viscosity of the solution in the emulsification homogenization process can be greatly reduced, and the obtained microcapsule liquid drop can be thinner. All of the components can increase the stability of the finally obtained nutrient microcapsule dry powder/particle product and have better bioavailability.
Detailed Description
The present invention is further illustrated by the following examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the present invention.
Example 1
60.7g (content: 82.4%) of lutein was weighed, 2.0g of mixed tocopherols was added, and dissolved with 1600 ml of tetrahydrofuran at 60 ℃ to obtain an oil phase.
8.0g of ascorbyl palmitate is taken and put into 400ml of water, and the temperature is raised to 40 ℃ and the mixture is stirred and dissolved to obtain a water phase. Adding the water phase into a shearing kettle, shearing and stirring, and slowly adding the oil phase to fully shear, mix and emulsify the oil phase and the water phase. After emulsification is finished, the temperature of the emulsion is 45 ℃, the viscosity is 68cPa, the emulsion is homogenized by a high-pressure homogenizer, the homogenizing pressure is 30MPa, and after homogenization is finished, the temperature of the emulsion is 52 ℃. The tetrahydrofuran was recovered under reduced pressure as an emulsion with dispersed xanthophylls as nano-sized droplets.
Under the condition of shearing and stirring, 450g of gelatin aqueous solution (containing 160.0g of gelatin and 120.0g of cane sugar) is added into the lutein-containing nano-scale droplet emulsion, and then shearing and stirring are carried out for 10min, and partial water is recovered to ensure that the solid content of the emulsion is 50%. Finally, 700g of an emulsion in which the average particle diameter of the droplets was 280nm as measured by a laser particle size distribution apparatus was obtained.
The lutein microcapsule particle is obtained by a spray-starch bed fluidized drying granulation process (the process can absorb about 60g of starch), wherein the lutein content is 12.5%.
The lutein microcapsule particle has good dispersibility in water, and the average particle diameter of emulsion drops after being dispersed in water is 326 nm. The particles themselves and after the tabletting treatment (compression 250MPa) have good stability. The microcapsule particles are packaged in an aluminum foil bag in a sealing way, and the stability data at 40 ℃ are shown in table 1.
Comparative example 2
Lutein 64.5g (content 82.4%) was weighed, 2.0g mixed tocopherol was added and dissolved with 1820 ml tetrahydrofuran at 60 ℃ to obtain an oil phase.
Taking 8.0g of ascorbyl palmitate, 160.0g of gelatin and 120.0g of cane sugar in 1000 ml of water, heating to 50 ℃, and stirring to dissolve to obtain a water phase. Adding the water phase into a shearing kettle, shearing and stirring, and slowly adding the oil phase to fully shear, mix and emulsify the oil phase and the water phase. After emulsification, the emulsion temperature is 65 ℃, the viscosity is 523.5cPa, and the emulsion is homogenized by a high-pressure homogenizer with the homogenizing pressure of 30 MPa. And decompressing and recovering tetrahydrofuran and partial water to obtain nano-scale emulsion of liquid drops, wherein floccules appear in the emulsion in the tetrahydrofuran recovery process, which indicates that partial gelatin is denatured and the viscosity of the emulsion is very high, and only a small amount of water can be recovered to ensure normal spray granulation, so that the solid content of the emulsion is only 36%. This gave 970g of emulsion in which the average diameter of the droplets was 1779nm, as determined by means of a laser particle size distribution apparatus.
The lutein microcapsule particle is obtained by a spray-starch bed fluidized drying granulation process (about 70g of starch is adsorbed in the process), wherein the lutein content is 11.8%.
The lutein particle has general dispersibility in water, obvious floccules can be seen in an aqueous solution after dispersion, and lutein crystals can be seen on the surface of the solution after the aqueous solution with the average emulsion droplet size of 1920nm is placed for one day after the dispersion in water. The particles themselves and after the tabletting treatment (compression 250MPa) are less stable. The microcapsule particles are packaged in an aluminum foil bag in a sealing way, and the stability data at 40 ℃ are shown in table 1.
As can be seen by comparison, in example 1, because the coating wall material gelatin is not added into the water phase before emulsification and homogenization, but only the lutein dissolved in tetrahydrofuran is subjected to high-speed shearing, the nanoscale droplets are formed by utilizing the emulsification and dispersion functions of a small amount of ascorbyl palmitate, the coating wall material gelatin is added immediately after the tetrahydrofuran is recovered, and the gelatin is fully coated around the formed lutein nanoscale droplets after shearing to form the microcapsule-state nanoscale droplets. In the process, the direct contact between the gelatin and the tetrahydrofuran solvent is avoided, and the damage effect of the organic solvent on the molecular structure of the gelatin is reduced, so that the good wrapping performance of the gelatin is kept. Meanwhile, due to the subsequent addition of the gelatin, the low viscosity of the water phase and the oil phase during shearing emulsification is ensured, so that the particle size of liquid drops in the emulsion can be finer. In the microcapsule particles of the final product, the average particle size of emulsion droplets is only 326nm, the emulsion particles with smaller particle size are beneficial to the stability of the final product, and the retention rate of the emulsion particles after being tabletted under high pressure and stored for three months is still more than 89%.
In contrast, in comparative example 2, the coating wall material was added before emulsification and homogenization, which not only increased the viscosity of the emulsion, but also made the tetrahydrofuran significantly destroy the gelatin, and the emulsion and homogenization appeared floccules after removal of the organic solvent, and the average particle size of the obtained droplets was only micron-sized. Moreover, the stability of the final product particles themselves and after tabletting was significantly inferior to the microcapsule product obtained in example 1.
TABLE 1 comparison of stability of lutein microcapsule microgranules obtained by different processes and their tabletting treatment (aluminum foil bag pack, 40 ℃ C.)
Example 3
45g of fish oil omega-3 fatty acid ethyl ester (34.2% of EPA, 22.6% of DHA, 59.4% of total omega-3 fatty acids), 3.0g of synthetic tocopherol and 100mL of acetone are added, and the mixture is uniformly stirred at 30 ℃ to obtain an oil phase. 15g of sorbitol palmitate was dissolved in 750ml of water at 40 ℃ to prepare an aqueous phase, and 3.5g of sodium ascorbate was added to the aqueous phase. Slowly adding the oil phase into the water phase under the condition of shearing, and shearing and mixing for 10min to obtain a well-mixed emulsion with the emulsion viscosity of 120 cPa. Homogenizing the obtained emulsion with homogenizer at 20Mpa, wherein the homogenization is easy to be carried out, the temperature of the emulsion is raised to 5 deg.C during the homogenization process, the acetone solvent is recovered under normal pressure, and the average particle diameter of the liquid drops in the obtained emulsion is 234 nm.
Under the condition of shearing, 150g of sodium octyl succinate starch (modified starch) is added into the emulsion after the solvent is recovered, shearing and mixing are kept for 10min, and spray drying is carried out to obtain the microcapsule dry powder containing fish oil omega-3 fatty acid ethyl ester.
The lutein microcapsule has average liquid drop size of 271nm after being dried and dispersed in water, good stability, and retention rate of over 86% after 3 months under the condition of 40 ℃ open after tabletting.
Examples 4 to 10
The objects and associated parameters for examples 4-10 are listed in table 2.
The invention is illustrated by the above examples, but it should be understood that the invention is not limited to the particular examples and embodiments described herein. These specific examples and embodiments are included to assist those skilled in the art in practicing the present invention. Further modifications and improvements will readily occur to those skilled in the art without departing from the spirit and scope of the invention and, accordingly, it is intended that the invention be limited only by the terms of the appended claims, along with the full scope of equivalents to which such terms are entitled.
Claims (17)
1. A preparation method of high-stability microcapsule of fat-soluble nutrient containing two or more double bonds comprises the following steps:
a) dissolving fat-soluble nutrient containing two or more double bonds in an organic solvent to prepare an oil phase;
b) dissolving an emulsion stabilizer in water to prepare a water phase;
c) shearing, mixing and emulsifying the water phase and the oil phase to obtain an emulsion;
d) homogenizing the obtained emulsion by a high-pressure homogenizer to ensure that the average particle size of liquid drops in the emulsion reaches the nanometer level;
e) recovering the organic solvent;
f) directly adding the aqueous solution of the coating wall material into the emulsion after the organic solvent is recovered, shearing, mixing and dissolving; and
g) the microcapsule dry powder or microcapsule particles with good stability are obtained after spray granulation and drying.
2. The preparation method according to claim 1, wherein the solvent temperature of the fat-soluble nutrient in the organic solvent in step a) is 20 to 100 ℃.
3. The method according to claim 1, wherein the ratio of the emulsion stabilizer to water in step b) is in the range of 30 to 250 times.
4. The method according to claim 1, wherein the temperature of the aqueous phase is 30-80 ℃ in step b).
5. The method according to claim 1, wherein the ratio of the water phase to the oil phase in step c) is in the range of 0.3 to 3.2.
6. The method according to claim 1, wherein the high-pressure homogenizing pressure in step d) is 20 to 60 MPa.
7. The method according to claim 1, wherein the ratio of water to the coating wall material is 0 to 2 times when the aqueous solution of the coating wall material is added in step f).
8. The preparation method according to claim 1, wherein the emulsion stabilizer is one or more of ascorbyl palmitate, mono-and di-glycerides, lecithin, sorbitol fatty acid ester and polyethylene glycol succinate.
9. The method according to claim 1, wherein the fat-soluble nutrient is one or more selected from the group consisting of vitamin A, vitamin E, vitamin D3, coenzyme Q10, curcumin, a carotenoid, and a polyunsaturated fatty acid.
10. The process according to claim 9, wherein the vitamin E is natural vitamin E and the coenzyme Q10 is reduced coenzyme Q10.
11. The method according to claim 9, wherein the carotenoid is one or more of beta-carotene, lutein, astaxanthin, lycopene and zeaxanthin.
12. The method according to claim 9, wherein the polyunsaturated fatty acid is one or more of an omega-3 polyunsaturated fatty acid derived from fish oil, an omega-3 polyunsaturated fatty acid derived from fermentation, conjugated linoleic acid, and arachidonic acid.
13. The method according to claim 1, wherein the organic solvent is dichloromethane, ethyl acetate, isobutyl acetate, acetone, ethanol, butanone, tetrahydrofuran, isobutanol, or isopropanol.
14. The method of claim 1, wherein the coated wall material is gelatin, gum arabic, modified starch or sodium caseinate.
15. The method according to claim 1, wherein an antioxidant is further added to the aqueous phase or the oil phase.
16. The method of claim 15, wherein the antioxidant is ascorbic acid, ascorbyl palmitate, mixed tocopherols, synthetic tocopherols, sodium ascorbate, lecithin or rosemary.
17. The process according to claim 1, wherein the spray granulation is spray drying, freeze drying or spray-starch bed fluidized drying.
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