WO2018036339A1 - 糖类微粒载体及其制备方法、使用方法和应用 - Google Patents

糖类微粒载体及其制备方法、使用方法和应用 Download PDF

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WO2018036339A1
WO2018036339A1 PCT/CN2017/094862 CN2017094862W WO2018036339A1 WO 2018036339 A1 WO2018036339 A1 WO 2018036339A1 CN 2017094862 W CN2017094862 W CN 2017094862W WO 2018036339 A1 WO2018036339 A1 WO 2018036339A1
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saccharide
carrier
microparticle
water
acid
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PCT/CN2017/094862
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English (en)
French (fr)
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谭淞文
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谭淞文
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/30—Foods or foodstuffs containing additives; Preparation or treatment thereof containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/20—Agglomerating; Granulating; Tabletting
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
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    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D53/00—Separation of gases or vapours; Recovering vapours of volatile solvents from gases; Chemical or biological purification of waste gases, e.g. engine exhaust gases, smoke, fumes, flue gases, aerosols
    • B01D53/02—Separation of gases or vapours; Recovering vapours of volatile solvents from gases; Chemical or biological purification of waste gases, e.g. engine exhaust gases, smoke, fumes, flue gases, aerosols by adsorption, e.g. preparative gas chromatography
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28016—Particle form
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
    • B01J20/28057—Surface area, e.g. B.E.T specific surface area
    • B01J20/28059—Surface area, e.g. B.E.T specific surface area being less than 100 m2/g
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J20/28078—Pore diameter
    • B01J20/2808—Pore diameter being less than 2 nm, i.e. micropores or nanopores
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
    • B01J20/28078—Pore diameter
    • B01J20/28083—Pore diameter being in the range 2-50 nm, i.e. mesopores
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J20/28078—Pore diameter
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    • A—HUMAN NECESSITIES
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    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention relates to the technical field of microparticle carriers, in particular to a saccharide microparticle carrier, a preparation method thereof, a using method and application thereof.
  • a carrier is a class of substances that can carry other substances or transfer energy. It is widely used in many fields, such as preparation of foods, drugs or spices, catalytic reactions, energy conservation and gas separation.
  • the drug or food carrier can change the manner in which the drug or food enters the body and the distribution in the body, control the release rate of the drug or food, and deliver the drug or food to the targeted organ.
  • Existing drugs or food carriers can reduce the degradation and loss of drugs or foods, reduce side effects, and improve bioavailability, but there are still problems such as low drug or food release efficiency, easy deterioration, difficulty in absorption, or high carrier preparation cost.
  • ginsenoside nanomicelle which is a non-saccharide carrier material which can widely adsorb various drugs. Since ginsenosides are soluble in water, the drug can be released after oral administration of the carrier, but ginsenoside needs to be extracted from ginseng, and the non-saccharide carrier is costly; and the water solubility of ginsenoside is much lower than that of the saccharide carrier, It affects the release efficiency of the drug after oral administration.
  • the prior art describes a polysaccharide-protein complex aggregate, which is a sugar-containing nanoparticle having a size of 50 to 300 nm and capable of adsorbing a large amount of foods which are poorly soluble in water, but during storage, since the food is Adsorbed on the surface of the particles, the food is easily degraded if it is in contact with the outside humid air; and after taking the carrier, the food will directly contact the complex environment of the gastrointestinal tract, which is prone to polymerization and precipitation, especially for substances with very low solubility. It is highly prone to polymerization precipitation and is not absorbed.
  • the present invention provides a saccharide microparticle carrier comprising three pores having different pore sizes, wherein the micropore pore diameter is less than or equal to 2 nm, the mesoporous pore diameter is 2 to 50 nm, and the macropore pore diameter is greater than or equal to 50 nm;
  • the pores, mesopores and macropores are uniformly distributed in the saccharide microparticle carrier;
  • the saccharide microparticle carrier is a flower-shaped structure, and the saccharide microparticle carrier has a specific surface area of 20 to 50 m 2 /g.
  • the saccharide microparticle carrier provided by the invention has a plurality of nanopore structures, and exhibits unique material properties, specifically manifesting in the ability of the micropores to limit the size of foreign substances and the transmission and storage capacity of the mesopores and macropores to foreign substances.
  • the micropores When adsorbing substances such as drugs or foods, the micropores will spatially restrict the adsorbed foreign molecules, and prevent the adsorbed substances from being polymerized and crystallized; most of the adsorbed and transported substances will be distributed in the middle layer of the carbohydrate particulate carrier, and the substances are located.
  • the adsorbed substances do not directly contact complicated environments such as the gastrointestinal tract, so as to avoid polymerization precipitation and increase the absorption rate of the substances.
  • the saccharide particulate carrier has a flower-like structure, has a large specific surface area of 20 to 50 m 2 /g, is highly soluble in water, can rapidly dissolve in water to release adsorbed substances, and can greatly enhance adsorbed substances such as drugs or foods.
  • the release efficiency and the absorption rate; and the saccharide particulate carrier can be stably present in air or an organic solvent, and is easy to store.
  • the saccharide microparticle carrier provided by the invention can be used as a water-soluble carrier to replace the existing chemical carrier to a certain extent, and can be widely used as a carrier for drugs or foods; and the particle with unique appearance is beneficial to the laboratory. It is studied that if the particles after adsorption of the drug have no fixed appearance, the positioning analysis cannot be performed, and the sugar particle carrier can display the distribution of the drug molecules in the particles by means of a confocal Raman analysis chart or the like, which is significant.
  • the saccharide microparticle carrier provided by the present invention improves the stability, release efficiency and absorption rate of the substance carried by the saccharide microparticle carrier by various nanopore structures of the saccharide microparticle carrier.
  • the present invention provides a method for preparing a saccharide microparticle carrier, comprising the steps of dissolving a saccharide substance and a water-fat double-soluble substance in water to obtain a mixture; and drying the obtained mixture; after spray drying The mixture is washed with an organic solvent; the washed mixture is dried at a constant temperature to a constant weight.
  • the saccharide is lactose, sucrose, fructose, mannose, starch, galactose, maltose, trehalose, glucose, ribose, xylose, fucose, rhamnose, arabinose, Sorbose, melibiose, chitosan and sugar derivatives mannitol, sorbitol, glucose alcohol, xylitol, polyethylene glycol, maltodextrin, cyclodextrin, amino acids, dextran, glucuronic acid Or one of acetazolamide, polymethacrylic acid, sodium cromoglycate, soybean polysaccharide, cellulose, cellulose ester, cellulose ether or Several; the water-fat double-soluble substance is one or more of citric acid, ascorbic acid, acetic acid, cetyltrimethylammonium bromide, polystyrene, boric acid, and lactic acid.
  • the temperature of the spray drying is from 150 to 250 °C.
  • the concentration of the spray dried mixture in the organic solvent is from 5 to 50 g/L.
  • the temperature of the constant temperature drying is 40 to 60 °C.
  • the preparation method of the saccharide microparticle carrier combines the template technique and the spray drying technique for the first time.
  • the templating technique uses a water-soluble double-soluble substance (soluble in water and an organic solvent) as a template, a water-soluble saccharide as a main material, a saccharide substance and a water-soluble double-soluble substance dissolved in water, a saccharide substance and a water-fat double
  • the content of the soluble substance can be adjusted according to different substances; then the obtained mixture is spray-dried to obtain dry particles, and the drying temperature can be adjusted according to different substances, and the drying humidity can be controlled according to the kind of the sugar substance to stabilize the humidity, and the drying time It is possible to control the crystallization of the finished product after drying in a suitable time according to the flow rate, preferably within 1 hour; the dry particles are washed with an organic solvent to remove the template in the mixture, leaving the porous saccharide carrier, after spray drying
  • the concentration of the mixture in the organic solvent can be adjusted according to the so
  • the material is a saccharide particulate carrier, and the saccharide microparticle carrier is between 1 and 30 microns in size.
  • Carbohydrate spray-dried particulate carrier size can be adjusted by the size of the nozzle.
  • the high-temperature spray drying method is commonly used in the field of milk powder production.
  • the present invention fully utilizes the advantages of high-temperature spray drying, combines it with template technology, and uses a sugar substance to prepare a sugar particle carrier, which is simple in production process and low in cost.
  • the prepared saccharide microparticle carrier has a plurality of nanopore structures, which improves the stability, release efficiency and absorption rate of the substance carried by the saccharide microparticle carrier.
  • the present invention provides a method for using a saccharide microparticle carrier, comprising the steps of: dissolving a drug or a food into an organic solvent, adding a saccharide microparticle carrier, stirring uniformly; and adsorbing the sugar of the drug or the food.
  • the particulate-like carrier is dried at room temperature.
  • the medicament is acetaminophen, indomethacin, nifedipine, paclitaxel, docetaxel, cabazitaxel, irinotecan hydrochloride, topotecan hydrochloride, hydroxycamptothecin , minoxidil, azithromycin, epirubicin hydrochloride, doxorubicin hydrochloride, amrubicin hydrochloride, tacrolimus, fluorouracil, vincristine sulfate, vinblastine sulfate, vindesine sulfate, vinorelbine tartrate Hama, Sequoia Alkali, homoharringtonine, harringtonine, epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, epothilone F Bortezomib, etoposide phosphate, gemcitabine hydrochlor
  • the saccharide particulate carrier is a water-soluble substance, and most of the drugs (such as acetaminophen, indomethacin, nifedipine and other poorly soluble western medicines, as well as water-soluble Chinese medicine ingredients), some foods (such as A fat-soluble vitamin or the like is a fat-soluble substance, and a drug or a food is dissolved in an organic solvent (such as an alcohol, an ether, a fat, a carbon tetrachloride, etc.), and the stirring time is controlled according to different kinds of substances, preferably 10 to 60 minutes, and sugar
  • the microparticle-like carrier serves as a carrier, and the nano-restricting ability of the micropores is used to collect the food or the drug dissolved in the organic solvent by air flotation, and then the saccharide microparticle carrier adsorbing the drug or the food is dried at room temperature to obtain a finished product.
  • the saccharide particulate carrier adsorbing the drug or the food is highly soluble in water due to its flower shape and large specific surface area, and can effectively improve the release efficiency and absorption rate of the drug or food.
  • the method for using the saccharide microparticle carrier provided by the invention has the advantages of simple operation, low cost, and the prepared finished product improves the water solubility of the poorly soluble drug or food, facilitates oral absorption, has good biological effect, and is inexpensive.
  • the stability, release efficiency and absorption rate of the drug or food carried by the saccharide microparticle carrier can be improved by using various nanopore structures of the saccharide microparticle carrier.
  • the present invention provides a saccharide particulate carrier for use in the preparation of foods, pharmaceuticals and fragrances, catalytic reactions, energy conservation and gas separation.
  • the porous particles provided by the prior art are inorganic or non-food grade organic materials, are inedible, and can only be used in the fields of perfume preparation, catalytic reaction, energy conservation or gas separation, and the sugar particle carrier prepared by the invention can be eaten. Therefore, it can be applied to drugs and food carriers for a wider range of uses.
  • FIG. 1 is a scanning electron micrograph, a pore area and a pore size distribution map of a saccharide particulate carrier according to a first embodiment of the present invention, and a scanning electron micrograph after focused ion dicing.
  • FIG. 2 is a flow chart showing a method for preparing a saccharide particulate carrier according to an embodiment of the present invention
  • Example 3 is a diagram showing a pore area and a pore radius distribution of a saccharide microparticle carrier prepared in Example 2 of the present invention
  • Example 4 is a diagram showing a pore area and a pore radius distribution of a saccharide microparticle carrier prepared in Example 3 of the present invention
  • Example 5 is a diagram showing a pore area and a pore radius distribution of a saccharide microparticle carrier prepared in Example 4 of the present invention
  • Figure 6 is a scanning electron micrograph and a confocal Raman scan of the saccharide particulate carrier after adsorption of acetaminophen in Example 5 of the present invention.
  • This embodiment provides a saccharide microparticle carrier comprising three pores having different pore sizes, wherein the micropore pore diameter is less than or equal to 2 nm, the mesoporous pore diameter is 2 to 50 nm, and the macropore pore diameter is greater than or equal to 50 nm; the micropore and the mesopores And the macropores are uniformly distributed in the saccharide microparticle carrier; the saccharide microparticle carrier is a flower-shaped structure, and the saccharide microparticle carrier has a specific surface area of 20 to 50 m 2 /g.
  • FIG. 1 is a scanning electron micrograph, a pore area and a pore size distribution map of a saccharide particulate carrier according to a first embodiment of the present invention, and a scanning electron micrograph after focused ion dicing.
  • the saccharide particle carrier has a flower-like spherical appearance.
  • the scanning electron micrograph after focused ion dicing can microscopically see the nanopore structure of the saccharide particle carrier, and the micropores, mesopores and macropores are evenly distributed.
  • the size and distribution of the different pores can be seen from the pore area and pore size distribution map.
  • FIG. 2 is a flow chart of a method for preparing a saccharide microparticle carrier according to an embodiment of the present invention, as shown in FIG.
  • the preparation method of the provided saccharide microparticle carrier comprises the following steps:
  • This embodiment provides a method for preparing a saccharide particulate carrier, comprising the following steps:
  • This embodiment provides a method for preparing a saccharide microparticle carrier, wherein the preparation method comprises the following steps:
  • This embodiment provides a method for preparing a saccharide microparticle carrier, wherein the preparation method comprises the following steps:
  • the saccharide microparticle carrier prepared according to the above second embodiment, the third embodiment or the fourth embodiment comprises three pores having different pore diameter ranges, wherein the micropore pore diameter is less than or equal to 2 nm, the mesoporous pore diameter is 2 to 50 nm, and the macropore pore diameter is It is greater than or equal to 50 nm; micropores, mesopores and macropores are uniformly distributed in the saccharide microparticle carrier; the saccharide microparticle carrier is a flower-shaped structure, and the saccharide microparticle carrier has a specific surface area of 20 to 50 m 2 /g.
  • Example 3 is a diagram showing the pore area and pore radius distribution of the saccharide microparticle carrier prepared in Example 2 of the present invention.
  • Example 4 is a diagram showing the pore area and pore radius distribution of the saccharide microparticle carrier prepared in Example 3 of the present invention.
  • Figure 5 is a diagram showing the pore area and pore radius distribution of the saccharide microparticle carrier prepared in Example 4 of the present invention.
  • the saccharide microparticle carrier is determined by a spectrophotometer, such as 0.1 mol/L acetaminophen, indomethacin and nifedipine, which are hardly soluble in water, and insoluble in water, vitamin A, vitamin D,
  • a fat-soluble food such as vitamin K can reach a mass fraction of 5 to 10%; for 0.5 mol/L of the above substances, the mass fraction can be 10-20%; for 1 mol/L of the above substances A mass fraction of 20% to 30% is achieved.
  • the saccharide microparticle carrier prepared by the second embodiment to the fourth embodiment has a multi-layer nanopore structure, and exhibits unique material properties, specifically showing the size limitation ability of the micropores to foreign substances and the mesopores and macropores to the outside. The ability to transport and store substances.
  • the micropores When adsorbing substances such as drugs or foods, the micropores will spatially limit the adsorbed foreign molecules, preventing the adsorbed substances from undergoing polymerization and crystallization; Most of the material will be distributed in the middle layer of the saccharide particle carrier.
  • the substance is located between the inner and outer layers, which is beneficial to avoiding the external environment directly, improving the stability of the adsorbed substance to prevent deterioration, and avoiding aggregation in the middle of the saccharide particle carrier.
  • the saccharide particulate carrier has a flower-shaped structure, has a large specific surface area, is highly soluble in water, can rapidly dissolve in water to release adsorbed substances, and can greatly improve the release efficiency and absorption rate of adsorbed substances such as drugs or foods; Moreover, the saccharide particulate carrier can be stably present in air or an organic solvent, and is easy to store. That is to say, according to the preparation method provided by the invention, the prepared saccharide microparticle carrier has a multi-layer nanopore structure, which improves the stability, release efficiency and absorption rate of the substance carried by the saccharide microparticle carrier.
  • saccharide particulate carrier prepared by using the parameters of the second embodiment has the best effect.
  • the saccharide particulate carrier prepared by other embodiments is also feasible.
  • other saccharides and their mass ratio, water-fat double-soluble substances and their mass ratio, spray drying temperature, organic solvent, spray-dried mixture in organic solvent are used.
  • the concentration in the medium and the constant temperature drying temperature are also feasible.
  • the mass of the water when the mixture is prepared by dissolving, the mass of the water is 100%, the mass of the saccharide is preferably 1 to 50%, and the mass of the water-soluble bisoluble substance is preferably 0.1 to 10%, because the saccharide is used.
  • the mass of the substance is less than 1%, the excessive moisture content will cause the crystallization rate to be too fast, the drying effect is extremely poor, and the sugar substance is limited by the solubility and the dissolution efficiency, preferably less than 50%, and the concentration of the saccharide substance.
  • the saccharide substance should be understood in a broad sense, including conventional saccharides such as lactose, sucrose, fructose, mannose, starch, galactose, maltose, trehalose, glucose, ribose, xylose, fucose, buckthorn.
  • sugar derivatives such as mann
  • the water-fat double-soluble substance is one or more of citric acid, ascorbic acid, acetic acid, cetyltrimethylammonium bromide, polystyrene, boric acid, and lactic acid, and is capable of being microscopically due to inorganic salts and the above-exemplified saccharides. It is soluble in organic solvents, so it can also be used as a water-soluble double-soluble substance.
  • the type of the saccharide or the water-fat double-soluble substance used for preparing the saccharide microparticle carrier is not limited to the above-listed species, and all the materials which can be used for preparing the saccharide microparticle carrier, the water-fat double-soluble substance and Organic solvents are all within the scope of the present invention.
  • the spray drying temperature is preferably from 150 to 250 ° C because the spray drying temperature is too low, the moisture removal ability is insufficient, the water content in the product is too high, or the drying effect is not obtained; and the temperature is too high to provide Excessive kinetic crystallization energy results in too fast crystallization, uneven product mixing and low yield.
  • the concentration of the spray-dried mixture in the organic solvent is preferably 5 to 50 g/L, considering that if the dry granules are too high, the organic solvent is relatively too small, resulting in failure to completely wash the stencil. Substance, the product is not pure; if the dosage is too low, the organic solvent is relatively too much, wastes too much solvent, and affects the particle morphology.
  • the temperature of the constant temperature drying is preferably 40 to 60 ° C, which is considered to be incapable of effectively removing moisture when the temperature of the constant temperature drying is lower than 40 ° C; and the morphology of the sugar particles is likely to change in the case of moisture when the temperature is higher than 60 ° C. .
  • the ambient pressure can be accelerated while the temperature is being dried at a constant temperature, the moisture removal can be accelerated, and a dry sample can be obtained by using a lower drying temperature, or the ambient pressure can be lowered while the constant temperature is dried to slow the moisture removal, and a higher drying temperature can be obtained. It is also possible to dry the sample, so that the temperature of the spray drying is below 40 ° C or above 60 ° C, and is also within the scope of the present invention.
  • the present invention devises a method of using the saccharide particulate carrier, comprising the steps of:
  • S6 The saccharide microparticle carrier to which the drug or the food is adsorbed is dried at room temperature.
  • This embodiment provides a method for using a saccharide particulate carrier, comprising the following steps:
  • S6 The saccharide microparticle carrier to which acetaminophen is adsorbed is dried at room temperature.
  • Figure 6 is a scanning electron micrograph and a confocal Raman scan of the saccharide particulate carrier after adsorption of acetaminophen in Example 5 of the present invention.
  • the saccharide microparticle carrier still has a flower-like appearance, and its appearance is basically unchanged after adsorption of acetaminophen (compared with the scanning electron micrograph of Fig. 1), which is beneficial to laboratory research. If the particles after adsorption of the drug have no fixed appearance, the positioning analysis cannot be performed, and the saccharide particle carrier can show the distribution of acetaminophen in the particles by means of a confocal Raman analysis chart or the like.
  • the confocal Raman scan map can characterize the molecular distribution of acetaminophen in the saccharide particulate carrier. It can be seen from the figure that most of the adsorbed acetaminophen is distributed in the red part of the saccharide particle carrier map, both inside and outside.
  • Adsorbed acetaminophen does not directly contact complex environments such as the gastrointestinal tract, so as to avoid polymerization precipitation and increase the absorption rate of acetaminophen.
  • the multi-layer nanopore structure of the saccharide microparticle carrier can improve the stability, release efficiency and absorption rate of the drug or food carried by the saccharide microparticle carrier.
  • the medicament is acetaminophen, indomethacin, nifedipine, paclitaxel, docetaxel, cabazitaxel, irinotecan hydrochloride, topotecan hydrochloride, Hydroxycamptothecin, minoxidil, azithromycin, epirubicin hydrochloride, doxorubicin hydrochloride, amrubicin hydrochloride, tacrolimus, fluorouracil, vincristine sulfate, vinblastine sulfate, vindesine sulfate , vinorelbine tartrate, huperzine A, homoharringtonine, harringtonine, epothilone A, epothilone B, epothilone C, epoth
  • the drug or food type in which the saccharide particulate carrier can be used is not limited to the above-listed species, and all the poorly water-soluble drugs or foods are within the scope of the present invention; and, the organic The kind of the solvent is also not limited to the above-listed species, and all of the organic solvents are within the scope of the present invention.
  • organic solvents low toxicity species such as methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol, fatty alcohol, n-nonanol, n-nonanol, n-undecyl alcohol are preferred.
  • n-dodecanol n-tetradecyl alcohol, n-hexadecanol, n-octadecyl alcohol, n-eicosyl alcohol, n-dodecanediol, octacosanol, triacontanol, 2- Propanol, 2-butanol, 2-hexanol, cyclohexanol, tert-butanol, trityl alcohol, 2-methyl-2-butanol, 2-methyl-1-propanol, 3-methyl- 1-butanol, pentane, formic acid, acetic acid, diethyl ether, acetone, anisole, butyl acetate, tributyl methyl ether, isopropyl acetate, methyl ethyl ketone, dimethyl sulfoxide, cumene, ethyl acetate, formic acid Ethyl ester,
  • This embodiment provides the use of a saccharide particulate carrier for the preparation of foods, pharmaceuticals and flavors, catalytic reactions, energy conservation and gas separation.
  • the porous particles provided by the prior art are inorganic or non-food grade organic materials, are inedible, and can only be used in the fields of perfume preparation, catalytic reaction, energy conservation or gas separation, and the sugar particle carrier prepared by the invention can be eaten. Therefore, it can be applied to drugs and food carriers for a wider range of uses.

Abstract

涉及一种糖类微粒载体及其制备方法、使用方法和应用，此糖类微粒载体包括三种孔径范围不同的孔，其中微孔孔径小于或等于2nm，中孔孔径为2～50nm，大孔孔径大于或等于50nm；所述微孔、所述中孔和所述大孔均匀分布在所述糖类微粒载体中；所述糖类微粒载体为花型结构，所述糖类微粒载体的比表面积为20～50m 2/g。提供糖类微粒载体及其制备方法、使用方法和应用，以提高载体运载的物质的稳定性、释放效率和吸收率。

Description

[根据细则37.2由ISA制定的发明名称]　糖类微粒载体及其制备方法、使用方法和应用 技术领域
本发明涉及微粒载体技术领域，具体涉及一种糖类微粒载体及其制备方法、使用方法和应用。
背景技术
载体是一类能够运载其他物质或传递能量的物质，它被广泛运用于多个领域，如制备食品、药物或香料，催化反应，能源保存和气体分离等。其中药物或食品载体能改变药物或食品进入人体的方式和在体内的分布，控制药物或食品的释放速度，并将药物或食品输送到靶向器官。现有的药物或食品载体虽可以减少药物或食品降解及损失，降低副作用，提高生物利用度，但是仍然存在药物或食品释放效率低、容易变质、不易吸收或载体制备成本较高等问题。
现有技术中记载了一种人参皂苷纳米胶束，它是一种非糖类载体材料，它能广泛吸附各种药物。由于人参皂苷能溶于水，口服该载体后，药物能够释放，但是人参皂苷需要从人参中提取，此种非糖类载体成本较高；而且人参皂苷的水溶性远低于糖类载体，严重影响了口服后药物的释放效率。
现有技术中记载了一种多糖-蛋白质复合聚集体，它是一种含糖的纳米颗粒，大小为50～300nm，能吸附大量难溶于水的食品，但是在保存时，由于食品都被吸附在颗粒的表面，食品若与外界潮湿空气接触则极易变质；而且人体在服用此种载体后，食品会直接接触胃肠道复杂环境，容易发生聚合沉淀，特别是对于溶解度非常小的物质，极易发生聚合沉淀而导致不被吸收。
因此，寻求新型的载体，以提高载体上的物质如药物或食品的稳定性、释放效率和吸收率，是当前需要解决的问题。
发明内容
针对现有技术中的缺陷，本发明目的在于提供一种糖类微粒载体及其制备方法、使用方法和应用，以提高载体运载的物质的稳定性、释放效率和吸收率。
为实现上述目的，本发明提供的技术方案为：
第一方面，本发明提供了一种糖类微粒载体，包括三种孔径范围不同的孔，其中微孔孔径小于或等于2nm，中孔孔径为2～50nm，大孔孔径大于或等于50nm；微孔、中孔和大孔均匀分布在所述糖类微粒载体中；糖类微粒载体为花型结构， 糖类微粒载体的比表面积为20～50m2/g。
本发明提供的糖类微粒载体，具有多种纳米孔结构，体现独特的材料特性，具体表现在微孔对外来物质的大小限制能力以及中孔、大孔对外来物质的传输储存能力。在吸附物质如药物或食品时，微孔会在空间上限制吸附的外来分子，可防止被吸附的物质发生聚合结晶；吸附传输进去的物质大部分会分布在糖类微粒载体的中层，物质位于内外层之间，既有利于直接避开外部环境，提高吸附的物质的稳定性防止变质，又避免聚集在糖类微粒载体的最中间，提高在水中的释放效率，且服用此种载体后，吸附的物质不会直接接触胃肠道等复杂环境，以免发生聚合沉淀，提高物质的吸收率。该糖类微粒载体为花型结构，具有很大的比表面积20～50m2/g，极易溶于水，能在水中快速溶解释放吸附的物质，可以大幅提高吸附的物质如药物或食品的释放效率和吸收率；且该糖类微粒载体能在空气或有机溶剂中稳定存在，易于保存。本发明提供的糖类微粒载体作为水溶性载体，可以在一定程度上替代现有的化学品载体，能广泛运用为药物或食品等物质的载体；并且这种有独特外貌的微粒有利于实验室研究，如果吸附药物后的颗粒没有固定外貌则无法进行定位分析，而该糖类微粒载体可借助共聚焦拉曼分析图等来显示药物分子在微粒中的分布情况，意义重大。
因此本发明提供的糖类微粒载体，通过糖类微粒载体的多种纳米孔结构，提高了糖类微粒载体运载的物质的稳定性、释放效率和吸收率。
第二方面，本发明提供了一种糖类微粒载体的制备方法，包括如下步骤：在水中溶解糖类物质和水脂双溶性物质，得到混合物；将得到的混合物进行喷雾干燥；将喷雾干燥后的混合物用有机溶剂洗涤；将洗涤后的混合物进行恒温干燥至恒重。
在本发明的进一步实施方式中，在溶解制备的混合物中，以水的质量为100％，糖类物质的质量为1～50％，水脂双溶性物质的质量为0.1～10％。
在本发明的进一步实施方式中，糖类物质为乳糖、蔗糖、果糖、甘露糖、淀粉、半乳糖、麦芽糖、海藻糖、葡萄糖、核糖、木糖、岩藻糖、鼠李糖、阿拉伯糖、山梨糖、蜜二糖、壳聚糖及糖类衍生物甘露醇、山梨糖醇、葡萄糖醇、木糖醇、聚乙二醇、麦芽糊精、环糊精、氨基酸、右旋糖酐、葡糖醛酸、乙酰唑胺、聚甲基丙烯酸、色甘酸钠、大豆多糖、纤维素、纤维素酯、纤维素醚中的一种或 几种；所述水脂双溶性物质为柠檬酸、抗坏血酸、乙酸、溴化十六烷基三甲铵、聚苯乙烯、硼酸和乳酸中的一种或几种。
在本发明的进一步实施方式中，喷雾干燥的温度为150～250℃。
在本发明的进一步实施方式中，喷雾干燥后的混合物在有机溶剂中的浓度为5～50g/L。
在本发明的进一步实施方式中，恒温干燥的温度为40～60℃。
本发明提供的糖类微粒载体的制备方法，首次将模板技术和喷雾干燥技术相结合。模板技术采用水脂双溶性物质(能溶于水和有机溶剂)为模板，水溶性糖类物质为主要材料，将糖类物质和水脂双溶性物质溶于水中，糖类物质和水脂双溶性物质的含量可以根据不同的物质调节；然后将得到的混合物进行喷雾干燥，得到干燥微粒，干燥温度可以根据不同的物质调节，干燥湿度可以根据糖类物质的种类控制在稳定的湿度，干燥时间可以根据流速控制在适当的时间内，要防止干燥后的成品结晶化，优选为1小时以内；将干燥微粒用有机溶剂洗涤，去除混合物中的模板，剩下多孔糖类微粒载体，喷雾干燥后的混合物在有机溶剂的浓度可以根据溶解度调节；将多孔糖类微粒载体进行恒温干燥，干燥时间和温度根据不同的糖类物质调节，干燥至恒重，干燥时间优选为3～5小时，干燥后的材料即为糖类微粒载体，糖类微粒载体大小在1～30微米之间，糖类微粒载体大小可通过喷雾干燥的喷头尺寸调节。高温喷雾干燥方式，常用于奶粉制作领域，本发明充分利用高温喷雾干燥的优点，将其与模板技术相结合，使用糖类物质，来制作糖类微粒载体，生产工艺简单，成本低。
采用本发明提供的制备方法，制备得到的糖类微粒载体具有多种纳米孔结构，提高了糖类微粒载体运载的物质的稳定性、释放效率和吸收率。
第三方面，本发明提供了一种糖类微粒载体的使用方法，包括如下步骤：将药物或食品溶入有机溶剂中，再加入糖类微粒载体，搅拌均匀；将吸附了药物或食品的糖类微粒载体室温干燥。
在本发明的进一步实施方式中，药物为对乙酰氨基酚、吲哚美辛、硝苯吡啶、紫杉醇、多西他赛、卡巴他赛、盐酸伊立替康、盐酸拓扑替康、羟喜树碱、米诺地尔、阿奇霉素、盐酸表柔比星、盐酸多柔比星、盐酸氨柔比星、他克莫司、氟尿嘧啶、硫酸长春新碱、硫酸长春碱、硫酸长春地辛、酒石酸长春瑞滨、石杉 碱甲、高三尖杉酯碱、三尖杉酯碱、埃博霉素A、埃博霉素B、埃博霉素C、埃博霉素D、埃博霉素E、埃博霉素F、硼替佐米、磷酸依托泊甙、盐酸吉西他滨、磷酸氟达拉滨、氟伐他汀、普伐他汀、辛伐他汀、洛伐他丁、美伐他汀、西立伐他汀、罗伐他汀、阿托伐他汀钙和瑞苏伐他汀钙中的一种或几种；食品为大豆异黄酮、小豆蔻明、白藜芦醇、辅酶Q10、维生素A、维生素D、维生素E、维生素K、银杏提取物、褪黑素、番茄红素和β-胡萝卜素中的一种或几种；有机溶剂为醇、醚、酯、四氯化碳、链烷烃、烯烃、醛、胺、酮、芳香烃、氢化烃、萜烯烃、卤代烃、杂环化物、含氮化合物和含硫化合物中的一种或几种。
糖类微粒载体为水溶性物质，而大部分药物(如对乙酰氨基酚、吲哚美辛、硝苯吡啶等难溶于水的西药，以及难溶于水的中药成分)、部分食品(如脂溶性维生素等)为脂溶性物质，将药物或食品溶入有机溶剂(如醇、醚、脂、四氯化碳等)中，搅拌时间根据不同物质种类控制，优选为10～60分钟，糖类微粒载体作为载体，通过微孔的纳米限制能力，气浮收集吸附溶解在有机溶剂中的食品或药物，然后将吸附了所述药物或食品的糖类微粒载体室温干燥，即可得到成品。吸附了药物或食品的糖类微粒载体由于具有花型外型和很大的比表面积，极易溶于水，可有效提高药物或食品的释放效率和吸收率。本发明提供的糖类微粒载体的使用方法，操作简便，成本低，且制备出的成品提高了难溶性药物或食品的水溶性，利于口服吸收，生物效果佳，且价格便宜。
采用本发明提供的糖类微粒载体的使用方法，利用糖类微粒载体的多种纳米孔结构，可提高糖类微粒载体运载的药物或食品的稳定性、释放效率和吸收率。
第四方面，本发明提供的糖类微粒载体在制备食品、药物和香料，催化反应，能源保存和气体分离中的应用。现有技术提供的多孔颗粒为无机物或非食品级有机物，不能食用，只能运用在香料制备、催化反应、能源保存或气体分离等领域，而本发明制备的糖类微粒载体，可以食用，因此还能运用于药物和食品载体，用途更为广泛。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
附图说明
图1为本发明实施例一中糖类微粒载体的扫描电镜图、孔面积和孔径分布图以及聚焦离子切割后的扫描电镜图。
图2为本发明实施例中的糖类微粒载体的制备方法的流程图；
图3为本发明实施例二中制备的糖类微粒载体的孔面积和孔半径分布图；
图4为本发明实施例三中制备的糖类微粒载体的孔面积和孔半径分布图；
图5为本发明实施例四中制备的糖类微粒载体的孔面积和孔半径分布图；
图6为本发明实施例五中糖类微粒载体在吸附对乙酰氨基酚后的扫描电镜图和共聚焦拉曼扫描图。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，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实施例，都属于本发明保护的范围。
实施例一
本实施例提供一种糖类微粒载体，包括三种孔径范围不同的孔，其中微孔孔径小于或等于2nm，中孔孔径为2～50nm，大孔孔径大于或等于50nm；微孔、中孔和大孔均匀分布在所述糖类微粒载体中；糖类微粒载体为花型结构，糖类微粒载体的比表面积为20～50m2/g。
图1为本发明实施例一中糖类微粒载体的扫描电镜图、孔面积和孔径分布图以及聚焦离子切割后的扫描电镜图。
从扫描电镜图中可以发现糖类微粒载体具有花型球状外貌，从聚焦离子切割后的扫描电镜图可显微可见糖类微粒载体的纳米孔结构，微孔、中孔和大孔均匀分布在糖类微粒载体中，从孔面积和孔径分布图可见不同孔的大小和分布情况。
针对本发明的糖类微粒载体，本发明设计了该糖类微粒载体的制备方法：图2为本发明实施例中的糖类微粒载体的制备方法的流程图，如图2所示，本发明提供的糖类微粒载体的制备方法，包括以下步骤：
S1：在水中溶解糖类物质和水脂双溶性物质，得到混合物；
S2：将所述混合物进行喷雾干燥；
S3：将所述喷雾干燥后的混合物用有机溶剂洗涤；
S4：将所述洗涤后的混合物进行恒温干燥至恒重。
下面结合具体实施例对本发明提供的糖类微粒载体的制备方法作进一步说明。
实施例二
本实施例提供了一种糖类微粒载体的制备方法，包括如下步骤：
S1：称取100g的水，加入10g乳糖和1g柠檬酸，溶解得到样品混合物；
S2：将得到的混合物进行喷雾干燥，干燥温度是150℃；
S3：将喷雾干燥后的混合物用乙醇洗涤，喷雾干燥后的混合物在乙醇中的浓度为25g/L，洗涤时间是30分钟；
S4：将洗涤后的混合物进行恒温干燥，干燥温度是50℃，干燥时间是3小时，干燥物质量恒定。
实施例三
本实施例提供了一种糖类微粒载体的制备方法，其中制备方法包括如下步骤：
S1：称取100g的水，加入10g甘露醇和2g柠檬酸，溶解得到样品混合物；
S2：将得到的混合物进行喷雾干燥，干燥温度是150℃；
S3：将喷雾干燥后的混合物用丙酮洗涤，喷雾干燥后的混合物在丙酮中的浓度为5g/L，洗涤时间是15分钟；
S4：将洗涤后的混合物进行恒温干燥，干燥温度是40℃，干燥时间是3小时至干燥物质量恒定。
实施例四
本实施例提供了一种糖类微粒载体的制备方法，其中制备方法包括如下步骤：
S1：称取100g的水，加入15g乳糖和2g硼酸，溶解得到样品混合物；
S2：将得到的混合物进行喷雾干燥，干燥温度是250℃；
S3：将喷雾干燥后的混合物用乙醇洗涤，喷雾干燥后的混合物在乙醇中的浓度为50g/L，洗涤时间是15分钟；
S4：将洗涤后的混合物进行恒温干燥，干燥温度是60℃，干燥时间是3小时至干燥物质量恒定。
根据上述实施例二、实施例三或实施例四制备得到的糖类微粒载体，包 括三种孔径范围不同的孔，其中微孔孔径小于或等于2nm，中孔孔径为2～50nm，大孔孔径大于或等于50nm；微孔、中孔和大孔均匀分布在所述糖类微粒载体中；糖类微粒载体为花型结构，糖类微粒载体的比表面积为20～50m2/g。
根据上述实施例二、实施例三或实施例四制备得到的糖类微粒载体的性能测定：
(1)糖类微粒载体的孔面积和孔半径分布情况
图3为本发明实施例二中制备得到的糖类微粒载体的孔面积和孔半径分布图。
图4为本发明实施例三中制备得到的糖类微粒载体的孔面积和孔半径分布图。
图5为本发明实施例四中制备得到的糖类微粒载体的孔面积和孔半径分布图。
(2)糖类微粒载体的吸附能力
通过分光光度计测定，糖类微粒载体对0.1mol/L的乙酰氨基酚、吲哚美辛和硝苯吡啶等难溶于水的西药，难溶于水的中药成分，维生素A、维生素D、维生素K等脂溶性食品能达到质量分数比为5～10％的吸附量；对0.5mol/L的上述物质能达到质量分数比为10～20％的吸附量；对1mol/L的上述物质能达到质量分数比为20％～30％的吸附量。
(3)吸附了食品或药物的糖类微粒载体的释放性能在模拟胃肠道低pH的模拟试验中，上述吸附了药物或食品的糖类微粒载体，能在10分钟内全部溶解，并有效释放质量分数比为70～100％的药物或食品到水溶液中，其中少部分在一定条件下因重结晶而不溶解。而传统方法，比如简单混合吸附药物或食品到糖类物质中，或通过物理化学手段制造的包括部分中、大孔结构的糖类载体，吸附药物或食品后，溶解在水中10分钟，仅能释放质量分数比为10～50％的药物或食品到水溶液中。此糖类载体技术能快速溶解，提高了非水溶性药物或食品的释放效率。
本发明实施例二至实施例四制备得到的糖类微粒载体，具有多层纳米孔结构，体现独特的材料特性，具体表现在微孔对外来物质的大小限制能力以及中孔、大孔对外来物质的传输储存能力。在吸附物质如药物或食品时，微孔会在空间上限制吸附的外来分子，可防止被吸附的物质发生聚合结晶；吸附传输进去的 物质大部分会分布在糖类微粒载体的中层，物质位于内外层之间，既有利于直接避开外部环境，提高吸附的物质的稳定性防止变质，又避免聚集在糖类微粒载体的最中间，提高在水中的释放效率，且服用此种载体后，吸附的物质不会直接接触胃肠道等复杂环境，以免发生聚合沉淀，提高物质的吸收率。该糖类微粒载体为花型结构，具有很大的比表面积，极易溶于水，能在水中快速溶解释放吸附的物质，可以大幅提高吸附的物质如药物或食品的释放效率和吸收率；且该糖类微粒载体能在空气或有机溶剂中稳定存在，易于保存。也就是说，采用本发明提供的制备方法，制备得到的糖类微粒载体具有多层纳米孔结构，提高了糖类微粒载体运载的物质的稳定性、释放效率和吸收率。
需要说明的是，运用实施例二的参数设置制备出来的糖类微粒载体的效果最佳，当然其他的实施例制备出来的糖类微粒载体也是可行的。除了实施例二至实施例四列举的情况，采用其他的糖类物质及其质量占比、水脂双溶性物质及其质量占比、喷雾干燥温度、有机溶剂、喷雾干燥后的混合物在有机溶剂中的浓度、恒温干燥温度也是可行的。
在本发明中，在溶解制备混合物时，以水的质量为100％，糖类物质的质量优选为1～50％，水脂双溶性物质的质量优选为0.1～10％，这是因为糖类物质的质量低于1％时，水分含量过多，会导致结晶速度太快，干燥效果极差，又因糖类物质受溶解度和溶解效率的限制，最好低于50％，糖类物质浓度过高会导致无法完全难溶；水脂双溶性物质含量若低于0.1％，起不到模版效果，产出物的孔隙率太低，水脂双溶性物质含量若高于10％，则会影响糖类物质在混合物种的比例，影响糖类物质的喷雾干燥效果，造成粘附、板结、低产量等系列问题。
在本发明中，糖类物质应该做广义理解，包括常规糖类如乳糖、蔗糖、果糖、甘露糖、淀粉、半乳糖、麦芽糖、海藻糖、葡萄糖、核糖、木糖、岩藻糖、鼠李糖、阿拉伯糖、山梨糖、蜜二糖、壳聚糖等；糖类衍生物如甘露醇、山梨糖醇、葡萄糖醇、木糖醇、聚乙二醇、麦芽糊精、环糊精、氨基酸、右旋糖酐、葡糖醛酸、乙酰唑胺、聚甲基丙烯酸、色甘酸钠、大豆多糖、纤维素、纤维素酯、纤维素醚，及其这些物质的衍生物、聚合物；动植物产品如牛奶、明胶、大豆蛋白、乳清蛋白、鸡蛋清、卵磷脂、咖啡、茶叶、吗啡、阿拉伯胶、甜菜果胶、琼脂、藻酸钠，及其这些物质的衍生物、聚合物；其他物质如蜡、石蜡、脂肪和油 等，制备糖类微粒载体时可选用上述列举的物质中的一种或几种。水脂双溶性物质为柠檬酸、抗坏血酸、乙酸、溴化十六烷基三甲铵、聚苯乙烯、硼酸和乳酸中的一种或几种，并且由于无机盐和上述列举的糖类物质能微溶于有机溶剂，所以也可以作为水脂双溶性物质。应该说明的是，用于制备糖类微粒载体的糖类物质或水脂双溶性物质种类并不限制于上述列举的种类，所有能用于制备糖类微粒载体的物质、水脂双溶性物质和有机溶剂均在本发明的保护范围之内。
在本发明中，喷雾干燥的温度优选为150～250℃，是因为喷雾干燥温度太低，水分去除能力不够，产品中含水量太高，或者达不到干燥效果；而温度太高则会提供过高的动力学结晶能量，导致结晶过快，产品混合不均且产量低。
但是由于在喷雾干燥的同时降低环境气压能加速水分去除，达到采用更低的干燥温度得到干燥样品，或者在喷雾干燥的同时升高环境气压能减慢水分去除，达到采用更高的干燥温度得到干燥样品，因此喷雾干燥的温度在150℃以下或250℃以上进行也是可行的，也在本发明的保护范围之内。
在本发明中，喷雾干燥后的混合物在有机溶剂中的浓度优选为5～50g/L，是考虑到若干燥颗粒投加量太高，则有机溶剂就相对太少，导致无法完全洗涤出模版物质，产品不纯；若投加量太低，则有机溶剂相对太多，浪费了过多溶剂，而且影响颗粒形态。
在本发明中，恒温干燥的温度优选为40～60℃，是考虑到恒温干燥的温度低于40℃就无法有效去除水分；高于60℃容易导致糖类微粒在潮湿的情况下形态发生变化。但是由于在恒温干燥的同时降低环境气压能加速水分去除，达到采用更低的干燥温度得到干燥样品，或者在恒温干燥的同时升高环境气压能减慢水分去除，达到采用更高的干燥温度得到干燥样品，因此喷雾干燥的温度在40℃以下或60℃以上进行也是可行的，也在本发明的保护范围之内。
针对本发明的糖类微粒载体，本发明设计了该糖类微粒载体的使用方法，包括以下步骤：
S5：将药物或食品溶入有机溶剂中，再加入所述糖类微粒载体，搅拌均匀；
S6：将吸附了所述药物或所述食品的糖类微粒载体室温干燥。
下面结合具体实施例对本发明提供的糖类微粒载体的使用方法作进一步说明。
实施例五
本实施例提供了一种糖类微粒载体的使用方法，包括如下步骤：
S5：将0.5mol对乙酰氨基酚溶入1L乙醇溶液中，再加入糖类微粒载体，搅拌均匀，吸附15分钟；
S6：将吸附了对乙酰氨基酚的糖类微粒载体进行室温干燥。
制备的吸附了对乙酰氨基酚的糖类微粒载体的性能测定：
图6为本发明实施例五中糖类微粒载体在吸附对乙酰氨基酚后的扫描电镜图和共聚焦拉曼扫描图。
从扫描电镜图中可以发现糖类微粒载体依然具有花型外貌，且在吸附对乙酰氨基酚后，其外型基本不变(与图1的扫描电镜图比较)，这有利于实验室研究，如果吸附药物后的颗粒没有固定外貌则无法进行定位分析，而该糖类微粒载体可借助共聚焦拉曼分析图等来显示对乙酰氨基酚在微粒中的分布情况。
共聚焦拉曼扫描图可表征对乙酰氨基酚在糖类微粒载体中的分子分布图，从图中可以发现吸附的对乙酰氨基酚大部分分布在糖类微粒载体图中的红色部分，在内外之间，既有利于直接避开外部环境，提高吸附的对乙酰氨基酚的稳定性防止变质，又避免聚集在糖类微粒载体的最中间，提高在水中的释放效率，且服用此种载体后，吸附的对乙酰氨基酚不会直接接触胃肠道等复杂环境，以免发生聚合沉淀，提高对乙酰氨基酚的吸收率。
采用本发明提供的糖类微粒载体的使用方法，利用糖类微粒载体的多层纳米孔结构，可提高糖类微粒载体运载的药物或食品的稳定性、释放效率和吸收率。
实施例六
本实施例提供了一种糖类微粒载体的使用方法，包括如下步骤：
S5：将0.8mol硝苯吡啶溶入1L丙酮溶液中，再加入糖类微粒载体，搅拌均匀，吸附15分钟；
S6：将吸附了硝苯吡啶的糖类微粒载体进行室温干燥。
实施例七
本实施例提供了一种糖类微粒载体的使用方法，包括如下步骤：
S5：将0.1mol吲哚美辛溶入1L乙醇溶液中，再加入糖类微粒载体，搅拌均匀， 吸附15分钟；
S6：将吸附了吲哚美辛的糖类微粒载体进行室温干燥。
需要说明的是，除了实施例五至实施例七列举的情况，采用其他的药物或食品、有机溶剂也是可行的。在本发明的糖类微粒载体的使用方法中，药物为对乙酰氨基酚、吲哚美辛、硝苯吡啶、紫杉醇、多西他赛、卡巴他赛、盐酸伊立替康、盐酸拓扑替康、羟喜树碱、米诺地尔、阿奇霉素、盐酸表柔比星、盐酸多柔比星、盐酸氨柔比星、他克莫司、氟尿嘧啶、硫酸长春新碱、硫酸长春碱、硫酸长春地辛、酒石酸长春瑞滨、石杉碱甲、高三尖杉酯碱、三尖杉酯碱、埃博霉素A、埃博霉素B、埃博霉素C、埃博霉素D、埃博霉素E、埃博霉素F、硼替佐米、磷酸依托泊甙、盐酸吉西他滨、磷酸氟达拉滨、氟伐他汀、普伐他汀、辛伐他汀、洛伐他丁、美伐他汀、西立伐他汀、罗伐他汀、阿托伐他汀钙和瑞苏伐他汀钙中的一种或几种；食品为大豆异黄酮、小豆蔻明、白藜芦醇、辅酶Q10、维生素A、维生素D、维生素E、维生素K、银杏提取物、褪黑素、番茄红素和β-胡萝卜素中的一种或几种；有机溶剂为醇、醚、酯、四氯化碳、链烷烃、烯烃、醛、胺、酮、芳香烃、氢化烃、萜烯烃、卤代烃、杂环化物、含氮化合物和含硫化合物中的一种或几种。需要说明的是，能运用糖类微粒载体的药物或食品种类并不限制于上述列举的种类，所有难溶于水的药物或食品均在本发明的保护范围之内；并且，所用到的有机溶剂的种类也并不限制于上述列举的种类，所有的有机溶剂均在本发明的保护范围之内。对于有机溶剂，优选低毒性的种类，如甲醇、乙醇、正丙醇、正丁醇、正戊醇、正己醇、正庚醇、脂肪醇、正壬醇、正癸醇、正十一烷醇、正十二烷醇、正十四烷醇、正十六烷醇、正十八烷醇、正二十烷醇、正二十二醇、二十八烷醇、三十烷醇、2－丙醇、2－丁醇、2－己醇、环己醇、叔丁醇、三苯甲醇、2－甲基－2－丁醇、2－甲基－1－丙醇、3－甲基－1－丁醇、戊烷、甲酸、乙酸、乙醚、丙酮、苯甲醚、乙酸丁酯、三丁甲基乙醚、乙酸异丙酯、甲乙酮、二甲亚砜、异丙基苯、乙酸乙酯、甲酸乙酯、乙酸异丁酯、乙酸甲酯、甲基异丁酮、乙酸丙酯、1，1－二乙氧基丙烷、1，1－二甲氧基甲烷、2，2－二甲氧基丙烷、异辛烷、异丙醚、甲基异丙酮、甲基四氢呋喃、石油醚、三氯乙酸、三氟乙酸和氯仿等中的一种或几种。
实施例八
本实施例提供的是糖类微粒载体在制备食品、药物和香料，催化反应，能源保存和气体分离中的应用。现有技术提供的多孔颗粒为无机物或非食品级有机物，不能食用，只能运用在香料制备、催化反应、能源保存或气体分离等领域，而本发明制备的糖类微粒载体，可以食用，因此还能运用于药物和食品载体，用途更为广泛。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型，而并不使相应技术方案的本质脱离本发明各实施例技术方案的范围，其均应涵盖在本发明的权利要求和说明书的范围当中。

Claims (10)

  1. 一种糖类微粒载体，其特征在于：包括三种孔径范围不同的孔，其中微孔孔径小于或等于2nm，中孔孔径为2～50nm，大孔孔径大于或等于50nm；所述微孔、所述中孔和所述大孔均匀分布在所述糖类微粒载体中；所述糖类微粒载体为花型结构，所述糖类微粒载体的比表面积为20～50m2/g。
  2. 一种制备权利要求1所述的糖类微粒载体的制备方法，其特征在于，包括如下步骤：在水中溶解糖类物质和水脂双溶性物质，得到混合物；将所述混合物进行喷雾干燥；将所述喷雾干燥后的混合物用有机溶剂洗涤；将所述洗涤后的混合物进行恒温干燥至恒重。
  3. 根据权利要求2所述的糖类微粒载体的制备方法，其特征在于：在溶解制备的所述混合物中，以所述水的质量为100％，所述糖类物质的质量为1～50％，所述水脂双溶性物质的质量为0.1～10％。
  4. 根据权利要求2所述的糖类微粒载体的制备方法，其特征在于：所述糖类物质为乳糖、蔗糖、果糖、甘露糖、淀粉、半乳糖、麦芽糖、海藻糖、葡萄糖、核糖、木糖、岩藻糖、鼠李糖、阿拉伯糖、山梨糖、蜜二糖、壳聚糖及糖类衍生物甘露醇、山梨糖醇、葡萄糖醇、木糖醇、聚乙二醇、麦芽糊精、环糊精、氨基酸、右旋糖酐、葡糖醛酸、乙酰唑胺、聚甲基丙烯酸、色甘酸钠、大豆多糖、纤维素、纤维素酯、纤维素醚中的一种或几种；所述水脂双溶性物质为柠檬酸、抗坏血酸、乙酸、溴化十六烷基三甲铵、聚苯乙烯、硼酸和乳酸中的一种或几种。
  5. 根据权利要求2所述的糖类微粒载体的制备方法，其特征在于：所述喷雾干燥的温度为150～250℃。
  6. 根据权利要求2所述的糖类微粒载体的制备方法，其特征在于：所述喷雾干燥后的混合物在所述有机溶剂中的浓度为5～50g/L。
  7. 根据权利要求2所述的糖类微粒载体的制备方法，其特征在于：所述恒温干燥的温度为40～60℃。
  8. 一种根据权利要求1所述的糖类微粒载体的使用方法，其特征在于，包括如下步骤：将药物或食品溶入有机溶剂中，再加入所述糖类微粒载体，搅拌均匀；将吸附了所述药物或所述食品的糖类微粒载体室温干燥。
  9. 根据权利要求8所述的糖类微粒载体的使用方法，其特征在于：所述药物为对乙酰氨基酚、吲哚美辛、硝苯吡啶、紫杉醇、多西他赛、卡巴他赛、盐酸伊立 替康、盐酸拓扑替康、羟喜树碱、米诺地尔、阿奇霉素、盐酸表柔比星、盐酸多柔比星、盐酸氨柔比星、他克莫司、氟尿嘧啶、硫酸长春新碱、硫酸长春碱、硫酸长春地辛、酒石酸长春瑞滨、石杉碱甲、高三尖杉酯碱、三尖杉酯碱、埃博霉素A、埃博霉素B、埃博霉素C、埃博霉素D、埃博霉素E、埃博霉素F、硼替佐米、磷酸依托泊甙、盐酸吉西他滨、磷酸氟达拉滨、氟伐他汀、普伐他汀、辛伐他汀、洛伐他丁、美伐他汀、西立伐他汀、罗伐他汀、阿托伐他汀钙和瑞苏伐他汀钙中的一种或几种；所述食品为维生素A、维生素D、维生素E、维生素K、大豆异黄酮、小豆蔻明、白藜芦醇、辅酶Q10、银杏提取物、褪黑素、番茄红素和β-胡萝卜素中的一种或几种；所述有机溶剂为醇、醚、酯、四氯化碳、链烷烃、烯烃、醛、胺、酮、芳香烃、氢化烃、萜烯烃、卤代烃、杂环化物、含氮化合物和含硫化合物中的一种或几种。
  10. 根据权利要求1所述的糖类微粒载体在制备食品、药物和香料，催化反应，能源保存和气体分离中的应用。
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