WO2020113811A1 - 含烟酰胺单核苷酸的生物高分子纳米球及其制备方法与应用 - Google Patents

含烟酰胺单核苷酸的生物高分子纳米球及其制备方法与应用 Download PDF

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WO2020113811A1
WO2020113811A1 PCT/CN2019/074219 CN2019074219W WO2020113811A1 WO 2020113811 A1 WO2020113811 A1 WO 2020113811A1 CN 2019074219 W CN2019074219 W CN 2019074219W WO 2020113811 A1 WO2020113811 A1 WO 2020113811A1
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biopolymer
nmn
nanosphere
parts
carrier
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PCT/CN2019/074219
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French (fr)
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王运
陈建生
李峰
段志刚
张波
刘喜元
方秋杰
胡珊
叶小舟
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泓博元生命科技（深圳）有限公司
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Priority to AU2021102577A priority Critical patent/AU2021102577A4/en

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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
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/13—Nucleic acids or derivatives thereof
    • 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
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention relates to the technical field of health care products, in particular to a biopolymer nanosphere containing NMN, a preparation, a preparation method and application thereof.
  • aging is a spontaneous inevitable process of organisms over time. It is a complex natural phenomenon. With the growth of age and the aging of the body, many health problems occur, which seriously affects people. In order to solve the above problems, drugs designed to delay aging and improve health or quality of life have been widely studied and popularized in recent years.
  • NMN nicotinamide mononucleotide
  • NAD nicotinamide adenine dinucleoside Acid, an important coenzyme for cell energy conversion.
  • NMN is a co-matrix for energy delivery in the respiratory chain. Clinical studies have shown that parenteral administration of NMN has a positive effect on the treatment of Parkinson's disease and major depression.
  • NMN is also a coenzyme for various hydrogen transfer enzymes (dehydrogenase, oxidoreductase), supporting the regeneration of brain, heart, blood vessel and muscle cells.
  • NAD nicotinamide adenine dinucleotide
  • NMN's chemical properties are unstable (requiring ready-to-use), making it difficult to be widely used.
  • the existing oral preparations containing NMN also have a low human absorption rate. Therefore, it is an urgent task to find a NMN material with stable production and high absorption efficiency.
  • the present invention provides a NMN-containing biopolymer nanosphere with high stability, easy storage, and large-scale production.
  • the invention provides a biopolymer nanosphere containing NMN, which includes a biopolymer carrier and NMN dispersed on the biopolymer carrier.
  • the invention also provides a method for preparing a biopolymer nanosphere containing NMN, which includes the following steps:
  • the NMN and the biopolymer carrier are mixed and stirred to obtain the NMN-containing biopolymer nanosphere, wherein NMN is dispersed on the biopolymer carrier.
  • the auxiliary material includes at least one of 0.05-30 parts of sodium alginate and 0.05-30 parts of xanthan gum.
  • the invention also provides an application of the NMN-containing biopolymer nanospheres in preparing medicines for preventing and treating sub-health and tumors and functional foods.
  • the invention also provides a pharmaceutical preparation comprising the biopolymer nanosphere containing NMN and pharmaceutically acceptable auxiliary materials;
  • the pharmaceutical preparation is one of tablets, capsules, granules, injections, tinctures, suppositories, patches, pills, syrups, mixtures, powders, lotions, films and dripping pills;
  • the pharmaceutical preparation is a capsule, and the capsule includes hard capsules and soft capsules.
  • the invention also provides a method for preparing the pharmaceutical preparation, which includes the following steps:
  • the method further includes tabletting the NMN-containing biopolymer nanosphere particles into tablets;
  • the method further includes filling the NMN-containing biopolymer nanosphere particles into a capsule shell to make a capsule;
  • the method further includes mixing the NMN-containing biopolymer nanosphere particles with edible oil and filling the soft capsule shell to make a soft capsule;
  • the granulation auxiliary material is at least one of microcrystalline cellulose, polyvinylpyrrolidone, sodium bicarbonate, magnesium stearate, calcium polyphosphate, wetting agent and binder.
  • the invention also provides a functional food comprising the NMN-containing biopolymer nanospheres and food additives.
  • the present invention has the advantages that the NMN-containing biopolymer nanospheres provided by the present invention have high stability, are easy to store, and can be mass-produced.
  • FIG. 1 is a preparation flow chart of NMN-containing biopolymer nanospheres in a preferred embodiment of the present invention.
  • Fig. 2 is a preparation flow chart of a pharmaceutical preparation in a preferred embodiment of the present invention.
  • Example 3 is a graph showing the release rate of the active ingredient after soaking in the simulated gastric acid solution and the simulated colon solution after the biopolymer nanospheres containing NMN in Example 2 of the present invention are made into tablets.
  • FIG. 4 is a graph showing the release rate of the active ingredient after the NMN-containing biopolymer nanospheres are formed into tablets after being immersed in a simulated colonic solution in FIG. 4 of the present invention.
  • a preferred embodiment of the present invention provides a biopolymer nanosphere containing NMN, which includes a biopolymer carrier and NMN dispersed on the biopolymer carrier.
  • the biopolymer carrier has a three-dimensional network structure, and the average particle size of the biopolymer carrier is 200-1000 nm.
  • the biopolymer carrier includes at least one of chitosan (CS) and konjac glucomannan (KGM).
  • KGM is a natural polymer soluble dietary fiber.
  • the fiber has a honeycomb three-dimensional interpenetrating network structure.
  • the size of the mesh is tens to thousands of nanometers.
  • NMN enters through the mesh and is loaded on the surface of the KGM fiber network.
  • the konjac glucomannan is at least one of konjac glucomannan, quaternized konjac glucomannan, carboxymethyl konjak glucomannan and deacetylated konjac glucomannan.
  • the biopolymer nanospheres include 1-20 parts of the NMN and 20-80 parts of the biopolymer carrier.
  • the biopolymer nanosphere further includes an auxiliary material, and the auxiliary material includes at least one of 0.05-30 parts of sodium alginate and 0.05-30 parts of xanthan gum in parts by weight.
  • Sodium alginate is a natural polysaccharide. It has the ability to concentrate solutions, form gels and form films. It can form a film structure on the outer surface of the biopolymer carrier. It has a waterproof and anti-oxidation effect and prevents NMN from being decomposed by light or oxygen. problem.
  • the average particle diameter of the biopolymer nanosphere is 500-1000 nm.
  • a preferred embodiment of the present invention further provides a method for preparing the biopolymer nanosphere containing NMN, which includes the following steps:
  • the molecular chain length and molecular weight of the biopolymer raw material are reduced, forming a honeycomb three-dimensional interpenetrating network structure and forming a cluster with an average particle size of 200-1000 nm Nanosphere.
  • the average particle size of the obtained NMN is 10-100 nm.
  • the order of addition between the NMN and the biopolymer carrier is in no particular order, and can be added in any order of addition.
  • step S12 the NMN is prepared by the following process:
  • nicotinamide phosphoribosyl transferase, ribose phosphate pyrophosphate kinase, ribose-5-phosphate isomerase, ribulose-3-phosphate isomerase, xylulose kinase and The reaction occurs under the catalysis of xylose isomerase to prepare the NMN.
  • a substrate solution is added to the reaction kettle, and the substrate solution contains 30 mM ATP, 30 mM xylose, 20 mM MgCl 2 , 10 mM KC1, and 100 mM Tris-HCl buffer, and the pH is adjusted to 7.5-8.0 .
  • the following catalytic enzymes ribose phosphate pyrophosphate kinase 6g/L substrate solution, ribose-5-phosphate isomerase 10g/L substrate solution, ribulose-3-phosphate isomerase llg/L substrate solution , Xylulose kinase 10g/L substrate solution and xylose isomerase 10g/L substrate solution.
  • the above reaction be carried out after 4h, the reaction solution was separated, and the reaction was further fed to the reaction kettle, nicotinamide To the reaction was added to 60mM, ZnCl 30mM of 2, Tris-HCl buffer and nicotinamide l00mM Phosphoribosyl transferase 15g/L substrate solution, stir evenly and continue the reaction. Continue stirring during the reaction (stirring speed 50rpm), control the reaction temperature at 35°C, maintain the pH at 7.5 ⁇ 8.0, and smoke after 4 hours of reaction The crude amide mononucleotide product solution (containing 12 mM NMN) is filtered, purified, and dried to obtain the finished nicotinamide mononucleotide product.
  • the invention also provides an application of the NMN-containing biopolymer nanospheres in preparing medicines for preventing and treating sub-health and tumors and functional foods.
  • the invention also provides a pharmaceutical preparation comprising the biopolymer nanosphere containing NMN and pharmaceutically acceptable auxiliary materials.
  • the pharmaceutical preparation is one of tablets, capsules, granules, injections, tinctures, suppositories, patches, pills, syrups, mixtures, powders, lotions, films, and pills.
  • the pharmaceutical preparation is a capsule, and the capsule includes hard capsules and soft capsules.
  • the pharmaceutically acceptable auxiliary materials include granulation auxiliary materials.
  • the granulation auxiliary material is at least one of microcrystalline cellulose, polyvinylpyrrolidone, sodium bicarbonate, magnesium stearate, calcium polyphosphate, wetting agent and binder.
  • a suitable daily dosage of NMN oral dosage form is 5 to 500 mg.
  • a suitable daily dosage of NMN oral dosage form is 25-100 mg.
  • a preferred embodiment of the present invention also provides a method for preparing the pharmaceutical preparation, which includes the following steps:
  • the method further includes tabletting the NMN-containing biopolymer nanosphere particles into tablets;
  • the method further includes filling the NMN-containing biopolymer nanosphere particles into a capsule shell to make a capsule;
  • the method further includes mixing the NMN-containing biopolymer nanosphere particles with edible oil and filling the soft capsule shell to make a soft capsule;
  • the granulation auxiliary material is at least one of microcrystalline cellulose, polyvinylpyrrolidone, sodium bicarbonate, magnesium stearate, calcium polyphosphate, wetting agent and binder.
  • the wetting agent includes one or two of 70% volumetric ethanol and water, and the binder includes pregelatinized starch with a mass concentration of 5-20%, and a starch slurry with a mass concentration of 10-15% And at least one of hypromellose solutions with a mass concentration of 10%.
  • the drying condition is vacuum drying at 10-50°C for 0.5-24 hours.
  • the order of addition between the NMN-containing biopolymer nanospheres and the granulation auxiliary materials is in no particular order, and can be added in any order of addition.
  • the preparation of the NMN-containing biopolymer nanospheres can be performed simultaneously with the preparation of the pharmaceutical preparation, that is, when the NMN is mixed with the biopolymer carrier, the granulation can be added The accessories are stirred together.
  • the invention also provides a functional food comprising the NMN-containing biopolymer nanospheres and food additives.
  • the food additives include pectin, fumaric acid, polydextrose, maltose, phospholipid, citric acid, hydroxypropyl starch, lactic acid, sorbitol, milk powder, maltodextrin, honey, corn starch, corn oil, sesame oil , Sucrose, vitamin C, vitamin E, xylitol and gelatin one or more.
  • the biopolymer nanosphere includes 20 parts of biopolymer carrier and 1 part of NMN in parts by weight.
  • the material of the biopolymer carrier is konjac glucomannan (KGM).
  • the NMN-containing biopolymer nanospheres also include auxiliary materials, and the auxiliary materials include 0.05 parts of sodium alginate in parts by weight.
  • biopolymer nanospheres are used to prepare a pharmaceutical preparation, which is a granule.
  • the granulation auxiliary materials include 12 parts of wetting agent and 4 parts of binder.
  • the wetting agent is Ethanol with a volume concentration of 70%
  • the binder is a starch slurry with a mass concentration of 10%;
  • the biopolymer nanospheres include 80 parts of biopolymer carrier and 20 parts of NMN, and the material of the biopolymer carrier is quaternized konjac glucomannan (QKGM) and The mixture of carboxymethyl konjac glucomannan (CKGM) has a mass ratio of 1:1.
  • the auxiliary material includes 30 parts of sodium alginate.
  • the quaternized konjac glucomannan (QKGM) and carboxymethyl konjac glucomannan (CKGM) are prepared from konjac glucomannan (KGM) through quaternization and carboxymethylation treatment, respectively.
  • the quaternized konjac glucomannan (QKGM) and carboxymethyl konjac glucomannan (CKGM) can also be stirred with a concentration of 0.1 to 1 mol/L HCl or 0.1 to 1 mol/L NaOH for 2 to 10 hours
  • the molecular weight of konjac glucomannan facilitates subsequent physical modification.
  • the pharmaceutical preparation is a tablet, and the tablet is prepared by the following method:
  • the granulation method described in Example 1 is used for granulation, and then the prepared granules are compressed with a tablet machine. By adjusting the parameters and pressure of the compression mold, the tablets with the target diameter, thickness and hardness can be prepared. Agent.
  • the granulation method of this embodiment is different from that of Embodiment 1 in that granulation auxiliary materials include 30 parts of binder, 25 parts of magnesium stearate and 30 parts of microcrystalline cellulose, wherein The binder is a mixture of pregelatinized starch with a mass concentration of 5% and hypromellose solution with a mass concentration of 10%.
  • the biopolymer nanospheres include 45 parts of biopolymer carrier and 5 parts of NMN, and the material of the biopolymer carrier is deacetylated konjac glucomannan (da-KGM) .
  • the auxiliary material includes 16 parts of sodium alginate.
  • the deacetylated konjac glucomannan (da-KGM) is prepared by deacetylation of KGM. Before step S11, the method further includes mixing the deacetylated konjac glucomannan (da-KGM) with a concentration of 0.1 to 1 mol/L HCl or 0.1 to 1 mol/L NaOH for 2 to 10 hours to reduce the konjac glucomannan
  • the molecular weight of sugar is convenient for subsequent physical modification.
  • the pharmaceutical preparation is a capsule, and the capsule is prepared by the following method:
  • the granulation method described in Example 1 is used for granulation, and after granulation, the prepared granules are filled into the shell of a commercially available edible hard capsule by a quantitative filling method to obtain a capsule preparation.
  • the granulation method of this example is different from that of Example 1 in that granulation auxiliary materials include 40 parts of binder, 0.5 parts of magnesium stearate, 0.5 parts of microcrystalline cellulose, 1 Parts of polyvinylpyrrolidone, 2 parts of sodium bicarbonate and 25 parts of wetting agent.
  • the wetting agent is ethanol with a volume concentration of 70%
  • the binder is a starch slurry with a mass concentration of 10%.
  • biopolymer nanospheres include 60 parts of biopolymer carrier and 5.2 parts of NMN.
  • the auxiliary material includes 30 parts of xanthan gum.
  • the method further includes stirring KGM with 0.1-1 mol/L HCl or 0.1-1 mol/L NaOH together for 2-10 hours to reduce the molecular weight of the konjac glucomannan to facilitate subsequent physical modification.
  • the pharmaceutical preparation is a soft capsule, and the soft capsule is prepared by the following method:
  • the granulation method described in Example 1 is used for granulation. After granulation, the prepared granules are mixed with an appropriate amount of edible oil and biosurfactant, and then encapsulated in a commercially available soft capsule shell to obtain a soft capsule preparation
  • the edible oil may be olive oil, sesame oil, soybean oil, corn oil, camellia oil, grape seed oil and the like.
  • the granulation method of this embodiment is different from that of Embodiment 1 in that granulation auxiliary materials are different.
  • the granulation auxiliary materials include 18 parts of binder, 2 parts of magnesium stearate, and 1 part of poly Calcium phosphate and 6 parts of wetting agent, wherein the wetting agent is 70% volume concentration of ethanol, and the binder is hypromellose solution with a mass concentration of 10%.
  • the biopolymer nanosphere includes 27 parts of biopolymer carrier and 9 parts of NMN.
  • the auxiliary material includes 0.05 parts of xanthan gum and 15 parts of sodium alginate.
  • the method further includes stirring KGM with 0.1-1 mol/L HCl or 0.1-1 mol/L NaOH together for 2-10 hours to reduce the molecular weight of the konjac glucomannan to facilitate subsequent physical modification.
  • the pharmaceutical preparation is a granule.
  • the granule is prepared by the method described in Example 1.
  • the difference is that the granulation auxiliary material includes 8 parts of binder and 10 parts of microcrystalline cellulose. And 15 parts of a wetting agent, wherein the wetting agent is a mixture of ethanol and water with a volume concentration of 70%, and the binder is pregelatinized starch with a mass concentration of 15%.
  • the biopolymer nanosphere includes 65 parts of biopolymer carrier and 13 parts of NMN, and the material of the biopolymer carrier is chitosan (CS).
  • the auxiliary material includes 15 parts of xanthan gum and 21 parts of sodium alginate.
  • the NMN-containing biopolymer nanospheres described in this example can be prepared by the preparation method of Example 1. The difference is that before step S11, the chitosan is further subjected to quaternization treatment for chemical modification to reduce the shell The molecular weight of glycan facilitates subsequent physical modification.
  • the granulation method described in Example 1 is used for granulation, and then the prepared granules are compressed with a tablet machine. By adjusting the parameters and pressure of the compression mold, the tablets with the target diameter, thickness and hardness can be prepared.
  • the granulation auxiliary material includes 16 parts of binder, 8 parts of microcrystalline cellulose, 10 parts of polyvinylpyrrolidone, 10 parts of sodium bicarbonate, and 13 parts of wetting agent, wherein the wetting agent is A mixture of ethanol and water with a volume concentration of 70%, and the binder is a starch slurry with a mass concentration of 10%.
  • the biopolymer nanospheres include 32 parts of biopolymer carrier and 5 parts of NMN, and the materials of the biopolymer carrier are konjac glucomannan (KGM) and chitosan (CS) mixture.
  • the auxiliary material includes 22 parts of xanthan gum and 7 parts of sodium alginate.
  • the material of the biopolymer carrier is chitosan (CS)
  • CS is a natural polymer material.
  • the material has a honeycomb three-dimensional interpenetrating network structure with a mesh size of tens to thousands Nanometer, NMN enters through the mesh and is loaded on the surface of the chitosan network.
  • the pharmaceutical preparation is a granule.
  • the granule is prepared by the method described in Example 1.
  • the difference is that: granulation auxiliary materials are different.
  • the granulation auxiliary materials include 8 parts of binder and 6 parts. Of microcrystalline cellulose, 3 parts of polyvinylpyrrolidone, 5 parts of sodium bicarbonate, 10 parts of magnesium stearate, 10 parts of calcium polyphosphate and 15 parts of wetting agent, wherein the wetting agent is A mixture of ethanol and water at a volume concentration of 70%, and the binder is a mixture of starch slurry at a mass concentration of 10% and pregelatinized starch at a mass concentration of 15%.
  • the pregelatinized starch in the granulation adjuvant in Example 2 not only has good disintegration and adhesion, but also significantly improves the hardness, disintegration and surface brightness of the tablet, and more importantly, it improves the dissolution rate.
  • the granulation difficulty is reduced, and the granulation and compressibility of the granules are improved.
  • the compressed tablets have high hardness, low brittleness and smooth surface.
  • Hydroxypropyl methylcellulose is a derivative of a mixed ether of hydroxypropyl and methoxycellulose. The replacement group in the molecule is an ether. It is used in tablets, mainly as a binder and a disintegrant. Disintegration improved and dissolution increased.
  • Microcrystalline cellulose has good fluidity and compressibility, and has both adhesive, lubricating, and disintegration-assisting properties. It has no interaction with drugs, and can make the tablet shape smooth, beautiful, and easy to disintegrate.
  • the test results are shown in Table 3 and FIG. 4.
  • Table 3 The release rate of the active ingredient after immersion in the simulated colon solution after the NMN-containing biopolymer nanospheres in Example 2 are made into tablets
  • the prepared preparation can release the NMN active ingredient within 8 to 10 hours after oral administration. It stays in the gastric juice and releases the active ingredient 2 hours before the preparation, and stays in the small intestine and releases the active ingredient after 6 to 8 hours.
  • the above test results show that the active ingredient NMN in the prepared tablet can be slowly released into the solution under the immersion of simulated gastric acid solution and simulated colon solution, and is a long-acting medicament.
  • Example 3 the microcrystalline cellulose in the excipient serves as a filler and a disintegrant, and polyvinylpyrrolidone plays a role in protecting and dispersing the drug, which is helpful for drug release.
  • the biopolymer nanosphere of the present invention includes a biopolymer carrier and NMN dispersed on the biopolymer carrier.
  • the biopolymer carrier is a polymer fiber polymer, and its fiber skeleton forms a three-dimensional interpenetrating network structure through random arrangement, cross arrangement, and crimp arrangement, so that the NMN is protected and its exposure to light or
  • the problem of easy decomposition after oxygen prolongs the storage time of NMN active ingredients and reduces the storage difficulty.
  • the biopolymer nanosphere of the present invention most of the NMN is dispersed inside the three-dimensional interpenetrating network of the biopolymer carrier, and a small part is loaded on the outer surface of the biopolymer carrier.
  • This three-dimensional interpenetrating network structure biopolymer carrier has the functions of biological activity and loading NMN active ingredients, so that the NMN loaded between the network structures is protected, and the problem that NMN is quickly decomposed by stomach acid and cannot be fully utilized is solved.
  • Is a polymer carrier with intestinal sustained-release effect, which provides an ideal drug carrier for NMN to treat diseases such as Parkinson's disease, Alzheimer's disease, depression and cancer. By slowly releasing the active ingredients of NMN and activating DNA repair enzymes to repair DNA, it can further prevent the occurrence of cancer.
  • the biopolymer carrier of the present invention is chitosan and/or konjac glucomannan.
  • Both chitosan and konjac glucomannan can form a honeycomb three-dimensional interpenetrating fiber network, which is easy to load NMN on Protected in the network.
  • konjac glucomannan is a natural polymer soluble dietary fiber with high viscosity, high water absorption and rapid expansion
  • chitosan is a natural polymer material with good biofunctionality, compatibility and safety And microbial degradability, and because of its positive charge, it also has a bacteriostatic effect.
  • the process for preparing the biopolymer nanospheres according to the present invention first prepares a physically modified biopolymer carrier, and mixes and grinds the biopolymer raw materials with xanthan gum and/or sodium alginate to Long biopolymer chains are cut into molecular chains of moderate length.
  • the physically modified biopolymer material has a moderate chain length, and it is easier to form spherical particles to form a honeycomb three-dimensional interpenetrating network structure, which is beneficial to the loading of NMN small molecules on the inner and outer surfaces of the network structure.
  • the physically modified biopolymer carrier has a membrane-like structure on its outer surface, which has the function of waterproofing and anti-oxidation. After sieving, the NMN is ground to a particle size of tens of nanometers, which makes it easier for NMN to enter the three-dimensional interpenetrating network structure of the biopolymer material and be protected.
  • the biopolymer nanospheres of the present invention can be applied to the preparation of tablets, granules, capsules, or soft capsules.
  • NMN is protected by a biopolymer carrier In the network structure, it is made into a pharmaceutical dosage form, so that the pharmaceutical preparation is slowly released in the intestine and is more easily absorbed by the human body, thereby improving the efficacy of the drug.
  • soft capsules disperse NMN-containing biopolymer nanospheres in the oil phase, isolating the contact of NMN with air and water, further solving the problem of easy decomposition of NMN, and having a longer shelf life.

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Abstract

一种含烟酰胺单核苷酸的生物高分子纳米球、其药物制剂或功能食品及制备方法和应用。该生物高分子纳米球包括生物高分子载体和分散于所述生物高分子载体上的烟酰胺单核苷酸，且生物高分子载体呈三维网络结构，平均粒径为200-1000nm，可用于制备防治亚健康、肿瘤的药物和功能食品。

Description

[根据细则37.2由ISA制定的发明名称]　含烟酰胺单核苷酸的生物高分子纳米球及其制备方法与应用 技术领域
本发明涉及保健产品技术领域，尤其涉及一种含NMN的生物高分子纳米球、制剂及其制备方法与应用。
背景技术
从生物学上讲，衰老是生物随着时间的推移，自发的必然过程，它是一种复杂的自然现象，随着年龄的增长以及机体的衰老，很多健康问题随之产生，严重影响了人们的生活质量，为解决上述问题，旨在延缓衰老、提高健康或生活质量的药物近年来已经获得了广泛研究和普及。
烟酰胺单核苷酸(NMN)的生物物质具有日益提高身体机能和智力表面的功效且无副作用，NMN在人体细胞能量生成中扮演重要角色，它参与细胞内NAD(烟酰胺腺嘌呤二核苷酸，细胞能量转化的重要辅酶)的合成。NMN是呼吸链中的能量递送共基质，临床研究显示肠外给予NMN对治疗帕金森病和重度抑郁症有积极作用。NMN还是各种氢转移酶(脱氢酶、氧化还原酶)的辅酶，支持脑，心脏，血管和肌肉细胞的再生。人体内的多个器官都会产生NMN，它能够转变为名为“烟酰胺腺嘌呤二核苷酸(NAD)”的核苷酸类辅酶，在过往的研究中已经证实，NAD能够使具有抗老化功能的蛋白质“Sirtuin”(去乙酰化酶)更为活跃；当人体衰老时体内NAD量会随之减少，而这种变化容易引发代谢机能下降及糖尿病等疾病。
但由于NMN高度敏感(对光和氧非常敏感)的特点，所以导致其化学性质不稳定(需即用即配)，使其难以广泛应用。此外，现有含NMN的口服制剂人体吸收率也较低。因此，寻找一种生产稳定且吸收效率高的NMN材 料是目前刻不容缓的事情。
发明内容
有鉴于此，本发明提供一种稳定性高、易保存、并可大规模生产的含NMN的生物高分子纳米球。
另，还有必要提供一种制备上述含NMN的生物高分子纳米球的方法以及上述含NMN的生物高分子纳米球的应用。
本发明提供一种含NMN的生物高分子纳米球，包括生物高分子载体和分散于所述生物高分子载体上的NMN。
本发明还提供一种制备含NMN的生物高分子纳米球的方法，包括如下步骤：
将生物高分子原料与辅料混合研磨以对所述生物高分子原料进行物理改性，得到生物高分子载体；
研磨NMN原料并过筛，得到NMN；
将所述NMN与所述生物高分子载体混合并搅拌，从而得到所述含NMN的生物高分子纳米球，其中，NMN分散于所述生物高分子载体上。
优选地，所述辅料包括0.05～30份的海藻酸钠以及0.05～30份的黄原胶中的至少一种。
本发明还提供一种所述含NMN的生物高分子纳米球在制备防治亚健康、肿瘤的药物以及功能食品中的应用。
本发明还提供一种药物制剂，包含所述含NMN的生物高分子纳米球和药学上可接受的辅料；
优选地，所述药物制剂为片剂、胶囊剂、颗粒剂、注射剂、酊剂、栓剂、贴剂、丸剂、糖浆剂、合剂、散剂、洗剂、膜剂及滴丸中的一种；
优选地，所述药物制剂为胶囊剂，所述胶囊剂包括硬胶囊剂和软胶囊剂。
本发明还提供一种制备所述药物制剂的方法，包括如下步骤：
提供所述含NMN的生物高分子纳米球，向所述生物高分子纳米球中添加制粒辅料并搅拌；
筛分制得粒径均一的颗粒湿料；
将所述颗粒湿料烘干，从而得到含NMN的生物高分子纳米球的颗粒；
优选地，所述方法还包括将所述含NMN的生物高分子纳米球颗粒进行压片，制成片剂；
优选地，所述方法还包括将所述含NMN的生物高分子纳米球颗粒填充入胶囊壳中，制成胶囊剂；
优选地，所述方法还包括将所述含NMN的生物高分子纳米球颗粒与食用油混合，填充于软胶囊壳中，制成软胶囊剂；
优选地，所述制粒辅料为微晶纤维素、聚乙烯吡咯烷酮、碳酸氢钠、硬脂酸镁、聚磷酸钙、润湿剂以及粘合剂中的至少一种。
本发明还提供一种功能食品，包含所述含NMN的生物高分子纳米球和食品添加剂。
本发明所具有的优点：本发明提供的所述含NMN的生物高分子纳米球稳定性高、易于保存，且可大规模生产。
附图说明
图1是本发明较佳实施例中的含NMN的生物高分子纳米球的制备流程图。
图2是本发明较佳实施例中的药物制剂的制备流程图。
图3是本发明实施例2中的含NMN的生物高分子纳米球制成片剂后在模拟胃酸溶液和模拟结肠溶液浸泡后有效成分的释放率趋势图。
图4是本发明实施例2中的含NMN的生物高分子纳米球制成片剂后在模拟结肠溶液浸泡后有效成分的释放率趋势图。
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作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。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。
本发明较佳实施方式提供一种含NMN的生物高分子纳米球，包括生物高分子载体和分散于所述生物高分子载体上的NMN。
所述生物高分子载体呈三维网络结构，所述生物高分子载体的平均粒径为200～1000nm。所述生物高分子载体包括壳聚糖(CS)以及魔芋葡甘聚糖(KGM)中的至少一种，KGM为天然高分子可溶性膳食纤维，该纤维呈蜂窝状三维互穿网络结构，网络结构的网孔大小为几十至上千纳米，NMN通过网孔进入并负载于KGM纤维网络表面。优选地，所述魔芋葡甘聚糖为魔芋葡甘聚糖、季铵化魔芋葡甘聚糖、羧甲基魔芋葡甘聚糖以及脱乙酰魔芋葡甘聚糖中的至少一种。以重量份计，所述生物高分子纳米球包括1～20份的所述NMN和20～80份的所述生物高分子载体。
优选地，所述生物高分子纳米球还包括辅料，以重量份计，所述辅料包括0.05～30份的海藻酸钠以及0.05～30份的黄原胶中的至少一种。海藻酸钠是一种天然多糖，具有浓缩溶液、形成凝胶和成膜的能力，可使生物高分子载体外表面形成膜层结构，具有防水防氧化作用，避免了NMN遇光或氧分解的问题。所述生物高分子纳米球的平均粒径为500～1000nm。
请参阅图1，本发明较佳实施方式还提供一种制备所述含NMN的生物高分子纳米球的方法，包括如下步骤：
S11、将生物高分子原料与辅料混合研磨，以对所述生物高分子原料进行 物理改性，得到生物高分子载体；
所述生物高分子原料与所述辅料混合研磨后会使所述生物高分子原料的分子链长度减小以及分子量降低，形成蜂窝状三维互穿网络结构并成团为平均粒径为200～1000nm的纳米球。
S12、研磨NMN原料并过筛，得到NMN；
得到的所述NMN的平均粒径为10～100nm。
S13、将所述NMN与所述生物高分子载体混合并搅拌，从而得到所述含NMN的生物高分子纳米球，其中，NMN分散于所述生物高分子载体上。
可以理解，在本发明中，所述NMN与所述生物高分子载体之间的加料顺序不分先后，可以以任意的加料顺序加入。
进一步地，步骤S12中NMN采用如下工艺制备：
以烟酰胺、ATP和木糖为原料，在烟酰胺磷酸核糖转移酶、核糖磷酸焦磷酸激酶、核糖-5-磷酸异构酶、核酮糖-3-磷酸异构酶、木酮糖激酶以及木糖异构酶的催化作用下发生反应，制得所述NMN。
具体地，向反应釜中加入底物溶液，所述底物溶液含30mM的ATP、30mM的木糖、20mM的MgCl 2、10mM的KC1以及l00mM的Tris-HCl缓冲液，调pH至7.5～8.0。然后加入以下催化用酶：核糖磷酸焦磷酸激酶6g/L底物溶液、核糖-5-磷酸异构酶10g/L底物溶液、核酮糖-3-磷酸异构酶l l g/L底物溶液、木酮糖激酶10g/L底物溶液以及木糖异构酶10g/L底物溶液。搅拌均匀后进行反应，反应过程中持续搅拌(搅拌速度50rpm)，控制反应温度为35℃，维持pH值为7.5～8.0。
待上述反应进行4h后，分离出反应液，并将反应液送入另一反应釜中，再向反应液中加入60mM的烟酰胺、30mM的ZnCl 2、l00mM的Tris-HCl缓冲液以及烟酰胺磷酸核糖转移酶15g/L底物溶液，搅拌均匀后继续反应，反应过程中持续搅拌(搅拌速度50rpm)，控制反应温度为35℃，维持pH值为7.5～8.0，再反应4h后即得烟酰胺单核苷酸粗产品溶液(含12mM的 NMN)，再经过滤、纯化、干燥后即得烟酰胺单核苷酸成品。
本发明还提供一种所述含NMN的生物高分子纳米球在制备防治亚健康、肿瘤的药物以及功能食品中的应用。
本发明还提供一种药物制剂，包含所述含NMN的生物高分子纳米球和药学上可接受的辅料。优选地，所述药物制剂为片剂、胶囊剂、颗粒剂、注射剂、酊剂、栓剂、贴剂、丸剂、糖浆剂、合剂、散剂、洗剂、膜剂及滴丸中的一种。优选地，所述药物制剂为胶囊剂，所述胶囊剂包括硬胶囊剂和软胶囊剂。所述药学上可接受的辅料包括制粒辅料。优选地，所述制粒辅料为微晶纤维素、聚乙烯吡咯烷酮、碳酸氢钠、硬脂酸镁、聚磷酸钙、润湿剂以及粘合剂中的至少一种。
优选地，NMN口服剂型的合适日剂量是5～500mg。优选地，NMN口服剂型的合适日剂量是25～100mg。
请参阅图2，本发明较佳实施方式还提供一种制备所述药物制剂的方法，包括如下步骤：
S21、提供所述含NMN的生物高分子纳米球，向所述生物高分子纳米球中添加制粒辅料并搅拌；
S22、筛分制得粒径均一的颗粒湿料；
S23、将所述颗粒湿料烘干，从而得到含NMN的生物高分子纳米球的颗粒。
优选地，所述方法还包括将所述含NMN的生物高分子纳米球颗粒进行压片，制成片剂；
优选地，所述方法还包括将所述含NMN的生物高分子纳米球颗粒填充入胶囊壳中，制成胶囊剂；
优选地，所述方法还包括将所述含NMN的生物高分子纳米球颗粒与食用油混合，填充于软胶囊壳中，制成软胶囊剂；
优选地，所述制粒辅料为微晶纤维素、聚乙烯吡咯烷酮、碳酸氢钠、硬 脂酸镁、聚磷酸钙、润湿剂以及粘合剂中的至少一种。
所述润湿剂包括体积浓度为70％的乙醇和水中的一种或两种，所述粘合剂包括质量浓度5～20％的预胶化淀粉、质量浓度为10～15％的淀粉浆以及质量浓度为10％的羟丙甲纤维素溶液中的至少一种。所述烘干的条件为在10～50℃下真空干燥0.5～24h。
可以理解，在本发明中，所述含NMN的生物高分子纳米球与所述制粒辅料之间的加料顺序不分先后，可以以任意的加料顺序加入。在本发明中，所述含NMN的生物高分子纳米球的制备可与所述药物制剂的制备同时进行，即，将所述NMN与所述生物高分子载体混合时，可加入所述制粒辅料共同搅拌。
本发明还提供一种功能食品，包含所述含NMN的生物高分子纳米球和食品添加剂。所述食品添加剂包括果胶、富马酸、聚葡萄糖、麦芽糖、磷脂、柠檬酸、羟丙基淀粉、乳酸、山梨糖醇、乳粉以、麦芽糊精、蜂蜜、玉米淀粉、玉米油、芝麻油、蔗糖、维生素C、维生素E、木糖醇以及明胶中的一种或几种。
下面通过实施例来对本发明进行具体说明。
实施例1
含NMN的生物高分子纳米球的制备：
S11、将魔芋葡甘聚糖(KGM)与海藻酸钠用胶体磨混磨，得到生物高分子载体。
S12、研磨NMN原料并过筛，得到NMN，所述NMN的平均粒径为10～100nm。
S13、将步骤S2得到的NMN与所述生物高分子载体混合并搅拌均匀，即得含NMN的生物高分子纳米球。所述生物高分子纳米球，以重量份计，包括20份的生物高分子载体和1份的NMN，所述生物高分子载体的材料为魔芋葡甘聚糖(KGM)。所述含NMN的生物高分子纳米球还包括辅料，以重 量份计，所述辅料包括0.05份的海藻酸钠。
使用上述生物高分子纳米球制备药物制剂，所述药物制剂为颗粒剂。
药物制剂的颗粒的制备：
S21、向含NMN的生物高分子纳米球中添加制粒辅料并搅拌，以重量份计，所述制粒辅料包括12份的润湿剂及4份的粘合剂，所述润湿剂为体积浓度为70％的乙醇，所述粘合剂为质量浓度10％的淀粉浆；
S22、用中号钢筛湿法制粒，即将称量好重量的物料置于筛孔尺寸由内而外递减的一套筛网上，物料按照颗粒大小分别留在各层筛面，得到颗粒湿料；
S23、烘干湿料，干燥温度为40℃，时间为3h，即得含NMN的生物高分子纳米球的颗粒。
实施例2
与实施例1不同的是：所述生物高分子纳米球包括80份的生物高分子载体和20份的NMN，所述生物高分子载体的材料为季铵化魔芋葡甘聚糖(QKGM)和羧甲基魔芋葡甘聚糖(CKGM)的混合物，二者的质量比为1：1。所述辅料包括30份的海藻酸钠。
所述季铵化魔芋葡甘聚糖(QKGM)和羧甲基魔芋葡甘聚糖(CKGM)分别由魔芋葡甘聚糖(KGM)经季胺化和羧甲基化处理制得。还可将季铵化魔芋葡甘聚糖(QKGM)和羧甲基魔芋葡甘聚糖(CKGM)与浓度0.1～1mol/L的HCl或0.1～1mol/L的NaOH共同搅拌2～10h，降低魔芋葡甘聚糖的分子量，方便后续物理改性。
所述药物制剂为片剂，所述片剂通过如下方法制备：
采用实施例1所述的制粒的方法制粒，然后将制得的颗粒用压片机压片处理，通过调节压片模具的参数及压力，即可制得目标直径、厚度和硬度的片剂。本实施例的制粒方法与实施例1的区别在于：制粒辅料不同，所述制粒辅料包括30份的粘合剂、25份的硬脂酸镁和30份的微晶纤维素，其中，所述粘合剂为质量浓度5％的预胶化淀粉和质量浓度为10％的羟丙甲纤维素 溶液混合物。
实施例3
与实施例1不同的是：所述生物高分子纳米球包括45份的生物高分子载体和5份的NMN，所述生物高分子载体的材料为脱乙酰魔芋葡甘聚糖(da-KGM)。所述辅料包括16份的海藻酸钠。
所述脱乙酰魔芋葡甘聚糖(da-KGM)由KGM经脱乙酰化处理制得。步骤S11前还包括将所述脱乙酰魔芋葡甘聚糖(da-KGM)与浓度0.1～1mol/L的HCl或0.1～1mol/L的NaOH共同搅拌2～10h，降低所述魔芋葡甘聚糖的分子量，方便后续物理改性。
所述药物制剂为胶囊剂，所述胶囊剂通过如下方法制备：
采用实施例1所述的制粒的方法制粒，制粒后，通过定量灌装的方法将制得的颗粒装入市售可食性硬胶囊外壳中，即得到胶囊制剂。本实施例的制粒方法与实施例1的区别在于：制粒辅料不同，所述制粒辅料包括40份的粘合剂、0.5份的硬脂酸镁、0.5份的微晶纤维素、1份的聚乙烯吡咯烷酮、2的份碳酸氢钠和25份的润湿剂。其中，所述润湿剂为体积浓度70％的乙醇，所述粘合剂为质量浓度10％的淀粉浆。
实施例4
与实施例1不同的是：所述生物高分子纳米球包括60份的生物高分子载体和5.2份的NMN。所述辅料包括30份的黄原胶。
步骤S11前还包括将KGM与浓度0.1～1mol/L的HCl或0.1～1mol/L的NaOH共同搅拌2～10h，降低所述魔芋葡甘聚糖的分子量，方便后续物理改性。
所述药物制剂为软胶囊剂，所述软胶囊剂通过如下方法制备：
采用实施例1所述的制粒的方法制粒，制粒后，将制得的颗粒与适量食用油、生物表面活性剂混合，然后封装至市售软胶囊外壳中，即制得软胶囊制剂，所述食用油可为橄榄油、芝麻油、大豆油、玉米油、山茶油以及葡萄 籽油等。本实施例的制粒方法与实施例1的区别在于：制粒辅料不同，本实施例中，所述制粒辅料包括18份的粘合剂、2份的硬脂酸镁、1份的聚磷酸钙以及6份的润湿剂，其中，所述润湿剂为体积浓度70％的乙醇，所述粘合剂为质量浓度10％的羟丙甲纤维素溶液。
实施例5
与实施例1不同的是：所述生物高分子纳米球包括27份的生物高分子载体和9份的NMN。所述辅料包括0.05份的黄原胶和15份的海藻酸钠。
步骤S11前还包括将KGM与浓度0.1～1mol/L的HCl或0.1～1mol/L的NaOH共同搅拌2～10h，降低所述魔芋葡甘聚糖的分子量，方便后续物理改性。
本实施例中，所述药物制剂为颗粒剂，所述颗粒剂通过实施例1所述的方法制备，区别在于：所述制粒辅料包括8份的粘合剂、10份的微晶纤维素以及15份的润湿剂，其中，所述润湿剂为体积浓度70％的乙醇和水的混合物，所述粘合剂为质量浓度15％的预胶化淀粉。
实施例6
与实施例1不同的是：所述生物高分子纳米球包括65份的生物高分子载体和13份的NMN，所述生物高分子载体的材料为壳聚糖(CS)。所述辅料包括15份的黄原胶和21份的海藻酸钠。
本实施例所述的含NMN的生物高分子纳米球可采用实施例1的制备方法制备，其区别在于，步骤S11前还包括对壳聚糖进行季胺化处理以进行化学改性，降低壳聚糖的分子量，方便后续物理改性。
采用实施例1所述的制粒的方法制粒，然后将制得的颗粒用压片机压片处理，通过调节压片模具的参数及压力，即可制得目标直径、厚度和硬度的片剂。所述制粒辅料包括16份的粘合剂、8份的微晶纤维素、10份的聚乙烯吡咯烷酮、10份的碳酸氢钠以及13份的润湿剂，其中，所述润湿剂为体积浓度70％的乙醇和水的混合物，所述粘合剂为质量浓度10％的淀粉浆。
实施例7
与实施例1不同的是：所述生物高分子纳米球包括32份的生物高分子载体和5份的NMN，所述生物高分子载体的材料为魔芋葡甘聚糖(KGM)与壳聚糖(CS)的混合物。所述辅料包括22份的黄原胶和7份的海藻酸钠。本实施例中，所述生物高分子载体的材料为壳聚糖(CS)，CS为天然高分子材料，该材料具有蜂窝状三维互穿网络结构，网络结构的网孔大小为几十至上千纳米，NMN通过网孔进入并负载于壳聚糖网络表面。
本实施例中，所述药物制剂为颗粒剂，所述颗粒剂通过实施例1所述的方法制备，区别在于：制粒辅料不同，所述制粒辅料包括8份的粘合剂、6份的微晶纤维素、3份的聚乙烯吡咯烷酮、5份的碳酸氢钠、10份的硬脂酸镁、10份的聚磷酸钙以及15份的润湿剂，其中，所述润湿剂为体积浓度70％的乙醇和水的混合物，所述粘合剂为质量浓度10％的淀粉浆与质量浓度15％的预胶化淀粉的混合物。
表1 本发明实施例1～7制备的含NMN的生物高分子纳米球及其具体处理条件
Figure PCTCN2019074219-appb-000001
Figure PCTCN2019074219-appb-000002
实施例2中制粒辅料中的预胶化淀粉，不仅具有良好的崩解、粘合作用，还可明显改善压片的硬度、崩解度与表面光亮度，更重要的是提高了溶出度，降低了制粒难度，提高了颗粒成粒性和可压性，压制的片剂硬度高、脆裂度小、表面光滑。羟丙基甲纤维素是羟丙基和甲氧基纤维素混合醚的衍生物，其分子内的置换基团是醚类，其用于片剂，主要作为粘合剂和崩解剂，使崩解改善、溶出度增加。微晶纤维素流动性和可压性好，兼具粘合、润滑和助崩解性能，与药物无相互作用，可使压片外形光洁美观、易崩解。
将实施例2制得的片剂在模拟胃酸溶液SGF pH＝2的条件下浸泡2h，然后在模拟结肠溶液SCF pH＝6.8的条件下浸泡6h，分别测试第2h、4h、6h以及8h NMN的释放率，测试结果如表2和图3所示。
表2 实施例2中的含NMN的生物高分子纳米球制成片剂后在模拟胃酸溶液和模拟结肠溶液浸泡后有效成分的释放率
时间h 释放率％
0 0
2 0.94
4 13.59
6 27.41
8 61.26
10 69.95
剩余量 8.08
将实施例2制得的片剂在模拟结肠溶液SCF pH＝6.8的条件下浸泡8h， 分别测试第2h、4h、6h以及8h NMN的释放率，测试结果如表3和图4所示。
表3 实施例2中的含NMN的生物高分子纳米球制成片剂后在模拟结肠溶液浸泡后有效成分的释放率
时间h 释放率％
0 0
2 39.34
4 64.23
6 81.54
8 83.55
剩余量 1.38
制得的制剂口服后可在8～10h内释放NMN有效成分，制剂前2h在胃液中停留并释放有效成分，后6～8h在小肠中停留并释放有效成分。上述测试结果表明，在模拟胃酸溶液和模拟结肠溶液浸泡下，制得的片剂中有效成分NMN可缓释至溶液中，是一种长效的药剂。
实施例3辅料中的微晶纤维素作为填充剂和崩解剂，聚乙烯吡咯烷酮起到保护药物和分散的作用，有助于药物的释放。
本发明的上述技术方案相比现有技术具有以下优点：
(1)本发明所述的生物高分子纳米球，包括生物高分子载体和分散于所述生物高分子载体上的NMN。所述生物高分子载体为高分子纤维聚合体，其纤维骨架通过无序排列、交叉排列、卷曲排列等排列方式，构成三维互穿网络结构，从而使得NMN得到了保护，解决了其遇光或氧后易分解的问题，延长了NMN有效成分的保存时间、降低了保存难度。
(2)本发明所述的生物高分子纳米球中，大部分NMN分散于生物高分子载体的三维互穿网络的内部，少部分负载于生物高分子载体外表面。这种三维互穿网络结构的生物高分子载体，兼具生物活性和负载NMN有效成分 的作用，使负载于网络结构间的NMN得到保护，解决了NMN遇胃酸快速分解、无法充分发挥效用的问题，是一种具有肠道缓释效果的高分子载体，为NMN治疗帕金森症、阿尔茨海默症、抑郁症以及癌症等疾病提供了一种理想的药物载体。通过缓释NMN有效成分，激活DNA修复酶对DNA进行修复，进一步还可以预防癌症的发生。
(3)本发明所述的生物高分子载体为壳聚糖和/或魔芋葡甘聚糖，壳聚糖以及魔芋葡甘聚糖均可形成蜂窝状三维互穿纤维网络，易于使NMN负载于网络中得到保护。其中，魔芋葡甘聚糖是一种天然的高分子可溶性膳食纤维，粘度高、吸水多、膨胀快；壳聚糖是一种天然高分子材料，具有良好的生物官能性和相容性、安全性和微生物降解性，且由于自身带有正电，还具有抑菌的作用。
(4)本发明所述的制备所述生物高分子纳米球的工艺，首先制备物理改性的生物高分子载体，通过将生物高分子原料与黄原胶和/或海藻酸钠混合研磨，将生物高分子长链截断为长度适中的分子链。物理改性后的生物高分子材料链长适中，更易形成球状颗粒，构成蜂窝状三维互穿网络结构，从而有利于NMN小分子负载于网络结构内外表面。另外，经过物理改性的生物高分子载体，其外表面形成了类似膜的结构，具有防水防氧化的作用，解决了NMN遇光和氧分解的问题，延长了NMN保存时间；通过研磨NMN原料并过筛处理，将NMN研磨至粒径为几十纳米，更易使NMN进入生物高分子材料的三维互穿网络结构中从而得到保护。
(5)本发明所述的生物高分子纳米球可应用于制备片剂、颗粒剂、胶囊或软胶囊等药剂，首先通过制备含NMN的生物高分子纳米球，使NMN由生物高分子载体保护于网络结构中，再制作为药物剂型，使得药物制剂在肠道缓释，更易被人体吸收，从而提高了药效。上述剂型中，软胶囊剂将含NMN的生物高分子纳米球分散于油相中，隔绝了NMN与空气和水的接触，进一步解决了NMN易分解的问题，具有更长的保质期。
以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或等同替换，而不脱离本发明技术方案的精神和实质。

Claims (11)

  1. 一种含NMN的生物高分子纳米球，其特征在于，包括生物高分子载体和分散于所述生物高分子载体上的NMN。
  2. 如权利要求1所述的含NMN的生物高分子纳米球，其特征在于，所述生物高分子载体呈三维网络结构，所述生物高分子载体的平均粒径为200～1000nm。
  3. 如权利要求1所述的含NMN的生物高分子纳米球，其特征在于，所述生物高分子载体包括魔芋葡甘聚糖以及壳聚糖中的至少一种；
    优选地，所述魔芋葡甘聚糖为魔芋葡甘聚糖、季铵化魔芋葡甘聚糖、羧甲基魔芋葡甘聚糖以及脱乙酰魔芋葡甘聚糖中的至少一种。
  4. 如权利要求1所述的含NMN的生物高分子纳米球，其特征在于，以重量份计，所述生物高分子纳米球包括1～20份的所述NMN以及20～80份的所述生物高分子载体。
  5. 如权利要求1所述的含NMN的生物高分子纳米球，其特征在于，所述生物高分子纳米球还包括辅料，以重量份计，所述辅料包括0.05～30份的海藻酸钠以及0.05～30份的黄原胶中的至少一种。
  6. 如权利要求1所述的含NMN的生物高分子纳米球，其特征在于，所述生物高分子纳米球的平均粒径为500～1000nm。
  7. 一种制备如权利要求1-6任一项所述的含NMN的生物高分子纳米球的方法，其特征在于，包括如下步骤：
    将生物高分子原料与辅料混合研磨，以对所述生物高分子原料进行物理改性，得到生物高分子载体；
    研磨NMN原料并过筛，得到NMN；
    将所述NMN与所述生物高分子载体混合并搅拌，从而得到所述含NMN的生物高分子纳米球，其中，NMN分散于所述生物高分子载体上；
    优选地，以重量份计，所述辅料包括0.05～30份的海藻酸钠以及0.05～30份的黄原胶中的至少一种。
  8. 一种如权利要求1-6任一项所述含NMN的生物高分子纳米球在制备防治亚健康、肿瘤的药物以及功能食品中的应用。
  9. 一种药物制剂，包含如权利要求1-6任一项所述的含NMN的生物高分子纳米球和药学上可接受的辅料；
    优选地，所述药物制剂为片剂、胶囊剂、颗粒剂、注射剂、酊剂、栓剂、贴剂、丸剂、糖浆剂、合剂、散剂、洗剂、膜剂以及滴丸中的一种；
    优选地，所述药物制剂为胶囊剂，所述胶囊剂包括硬胶囊剂和软胶囊剂。
  10. 一种制备如权利要求9所述的药物制剂的方法，其特征在于，包括如下步骤：
    提供所述含NMN的生物高分子纳米球，向所述生物高分子纳米球中添加制粒辅料并搅拌；
    筛分制得粒径均一的颗粒湿料；
    将所述颗粒湿料烘干，从而得到含NMN的生物高分子纳米球的颗粒；
    优选地，所述方法还包括将所述含NMN的生物高分子纳米球颗粒进行压片，制成片剂；
    优选地，所述方法还包括将所述含NMN的生物高分子纳米球颗粒填充入胶囊壳中，制成胶囊剂；
    优选地，所述方法还包括将所述含NMN的生物高分子纳米球颗粒与食用油混合，填充于软胶囊壳中，制成软胶囊剂；
    优选地，所述制粒辅料为微晶纤维素、聚乙烯吡咯烷酮、碳酸氢钠、硬脂酸镁、聚磷酸钙、润湿剂以及粘合剂中的至少一种。
  11. 一种功能食品，包含如权利要求1-6任一项所述的含NMN的生物高分子纳米球和食品添加剂。
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