WO2020113812A1 - Nanosphère biologique de poids moléculaire élevé contenant du nadh, son procédé de préparation et ses applications - Google Patents

Nanosphère biologique de poids moléculaire élevé contenant du nadh, son procédé de préparation et ses applications Download PDF

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WO2020113812A1
WO2020113812A1 PCT/CN2019/074220 CN2019074220W WO2020113812A1 WO 2020113812 A1 WO2020113812 A1 WO 2020113812A1 CN 2019074220 W CN2019074220 W CN 2019074220W WO 2020113812 A1 WO2020113812 A1 WO 2020113812A1
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nadh
biopolymer
nanosphere
parts
carrier
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PCT/CN2019/074220
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Chinese (zh)
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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 AU2021102578A priority Critical patent/AU2021102578A4/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
    • A61K9/14—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
    • A61K9/146—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 macromolecular compounds
    • 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
    • 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
    • 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
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • A23L33/25—Synthetic polymers, e.g. vinylic or acrylic polymers
    • A23L33/26—Polyol polyesters, e.g. sucrose polyesters; Synthetic sugar polymers, e.g. polydextrose
    • 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
    • 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
    • A23P10/28—Tabletting; Making food bars by compression of a dry powdered mixture
    • 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
    • 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
    • A23P10/35—Encapsulation of particles, e.g. foodstuff additives with oils, lipids, monoglycerides or diglycerides
    • 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
    • A23P20/00—Coating of foodstuffs; Coatings therefor; Making laminated, multi-layered, stuffed or hollow foodstuffs
    • A23P20/20—Making of laminated, multi-layered, stuffed or hollow foodstuffs, e.g. by wrapping in preformed edible dough sheets or in edible food containers
    • A23P20/25—Filling or stuffing cored food pieces, e.g. combined with coring or making cavities
    • 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
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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 NADH and a preparation method and application thereof.
  • NADH nicotinamide adenine dinucleotide
  • NADH serves as an electron donor and has oxidation during hundreds of thousands of metabolic reactions in living cells. The reduction activity plays an important role in electron transfer during glycolysis, citric acid cycle and photosynthesis.
  • NADH is involved in vitamin derivation and the production of adenosine triphosphate (ATP), and is a coenzyme of more than 250 dehydrogenases that have been identified, and has the role of maintaining cell growth, differentiation and energy metabolism.
  • ATP adenosine triphosphate
  • NADH is considered to have beneficial effects on the body and intelligence without side effects. It can be used as a drug to improve health and quality of life. Clinical studies have shown that parenteral administration of NADH has a positive effect on the treatment of Parkinson's disease and major depression. NADH can promote the cognitive ability and exercise ability of patients with Parkinson's disease and Alzheimer's disease, and at the same time relieve fatigue, drowsiness, pigmented fatigue syndrome, and enhance the vitality of users.
  • NADH has successfully treated various neurological diseases such as Parkinson's disease, Alzheimer's disease and delayed dementia by infusion, but due to the high sensitivity of NADH liquid (very sensitive to light and oxygen), As a result, its chemical properties are unstable (requiring ready-to-use), which has not been widely used. In addition, NADH is decomposed immediately after contact with gastric acid, which makes oral administration impossible.
  • the present invention provides a NADH-containing biopolymer nanosphere with good stability, easy storage, oral administration, and mass production.
  • the invention provides a biopolymer nanosphere containing NADH, which includes a biopolymer carrier and NADH dispersed on the biopolymer carrier.
  • the invention also provides a method for preparing biopolymer nanospheres containing NADH, including the following steps:
  • the NADH and the biopolymer carrier are mixed and stirred to obtain the NADH-containing biopolymer nanosphere, wherein NADH 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 NADH-containing biopolymer nanospheres in the preparation of drugs for preventing and treating sub-health and tumors and functional foods.
  • the invention also provides a pharmaceutical preparation comprising the NADH-containing biopolymer nanospheres 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 NADH-containing biopolymer nanosphere particles into tablets;
  • the method further includes filling the NADH-containing biopolymer nanosphere particles into a capsule shell to make a capsule;
  • the method further comprises mixing the NADH-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 NADH-containing biopolymer nanospheres and food additives.
  • the advantages of the present invention extend the storage time of NADH active ingredients, reduce storage difficulty, improve stability, and maintain biological activity.
  • FIG. 1 is a preparation flow chart of NADH-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.
  • FIG. 3 is an XRD test chart of NADH-containing biopolymer nanospheres under different NADH contents in a preferred embodiment of the present invention.
  • 4A and 4B are scanning electron microscope images of NADH-containing biopolymer nanospheres in Example 1 of the present invention.
  • Example 5 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 NADH-containing biopolymer nanospheres are formed into tablets in Example 2 of the present invention.
  • Example 6 is a graph showing the release rate of the active ingredient after the NADH-containing biopolymer nanospheres in Example 2 of the present invention are formed into tablets and soaked in a simulated colon solution.
  • a preferred embodiment of the present invention provides a NADH-containing biopolymer nanosphere, which includes a biopolymer carrier and NADH 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, NADH 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 NADH 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 avoids NADH 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 NADH-containing biopolymer nanospheres, including 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 diameter of the obtained NADH is 10 to 100 nm.
  • the order of addition between the NADH and the biopolymer carrier is in no particular order, and can be added in any order of addition.
  • step S13 Adjust the addition amount of NADH in step S13, and detect the NADH-containing biopolymer nanospheres with different NADH contents (0%, 8%, and 10%) by X-ray diffraction (XRD) to obtain XRD as shown in FIG. 3 Diffraction pattern, as can be seen from Fig.
  • XRD X-ray diffraction
  • the biopolymer carrier (blank microspheres) without NADH loading exhibited broad diffraction peaks of polysaccharide cellulose (diffraction peaks at 2 ⁇ angles of 18° and 22.5°), After loading NADH, several new diffraction peaks appeared, which are characteristic diffraction peaks of NADH, and the intensity of XRD diffraction peak of nanospheres containing 10% NADH is higher than that of nanospheres containing 8% NADH, which further proves that NADH has succeeded Loaded on biopolymer carrier.
  • NADH raw material in step S12 is prepared by the following process:
  • the NADH raw material is prepared by catalyzing with immobilized recombinant nicotinamide riboside adenylyl transferase, using nicotinamide nucleotide and adenosine triphosphate (ATP) as substrates.
  • the bacterial cells were lysed with ultrasonic waves, centrifuged (17°C, 10800 g, 10 min) and the supernatant was collected as crude protein extract (or crude extract).
  • the crude nicotinamide riboside adenylyl transferase crude protein was heat-treated at 70°C for 10 min, centrifuged (10°C, 17800 g, 10 min), and the supernatant was collected as the partially purified protein.
  • the specific steps for preparing the NADH raw material with immobilized nicotinamide riboside adenylyl transferase in S123 are as follows: preparing a substrate solution: containing 5 mM nicotinamide nucleotide, 10 mM disodium adenosine triphosphate (ATP), 100 mM Tris hydrochloric acid The buffer and MgCl 2 at a final concentration of 10 mM were adjusted to pH 7.5. Take 1 mL of the substrate solution, then add 0.05 g of immobilized nicotinamide riboside adenylyl transferase, and perform the reaction at 37°C for 2 to 20 hours.
  • the invention also provides an application of the NADH-containing biopolymer nanospheres in the preparation of drugs for preventing and treating sub-health and tumors and functional foods.
  • the invention also provides a pharmaceutical preparation comprising the NADH-containing biopolymer nanospheres and pharmaceutically acceptable excipients.
  • 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 NADH oral dosage form is 5 to 500 mg.
  • a suitable daily dosage of NADH 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 NADH-containing biopolymer nanosphere particles into tablets;
  • the method further includes filling the NADH-containing biopolymer nanosphere particles into a capsule shell to make a capsule;
  • the method further comprises mixing the NADH-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 NADH-containing biopolymer nanospheres and the granulation auxiliary materials is in no particular order, and they can be added in any order of addition.
  • the preparation of the NADH-containing biopolymer nanospheres can be performed simultaneously with the preparation of the pharmaceutical preparation, that is, when the NADH 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 NADH-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 average particle diameter of the NADH is 10-100 nm.
  • the NADH obtained in step S12 is mixed with the biopolymer carrier and stirred evenly to obtain a biopolymer nanosphere containing NADH.
  • the biopolymer nanospheres include 20 parts of biopolymer carrier and 1 part of NADH in parts by weight.
  • the material of the biopolymer carrier is konjac glucomannan (KGM).
  • the NADH-containing biopolymer nanospheres further include an auxiliary material, and the auxiliary material includes 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 10 parts of wetting agent and 5 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 NADH, 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 example is different from that in Example 1 in that granulation auxiliary materials include 40 parts of binder, 30 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 NADH, and the material of the biopolymer carrier is deacetylated konjac glucomannan (da-KGM) .
  • the auxiliary material includes 15 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 20 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 20 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 NADH.
  • 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, etc.
  • 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 16 parts of binder, 2 parts of magnesium stearate, and 1 part of poly Calcium phosphate and 15 parts of wetting agent, wherein the wetting agent is ethanol with a volume concentration of 70%, and the binder is hypromellose solution with a mass concentration of 10%.
  • the biopolymer nanospheres include 40 parts of biopolymer carrier and 12 parts of NADH.
  • the auxiliary material includes 0.05 parts of xanthan gum and 13 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 5 parts of binder and 12 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 70 parts of biopolymer carrier and 15 parts of NADH, and the material of the biopolymer carrier is chitosan (CS).
  • the auxiliary material includes 15 parts of xanthan gum and 24 parts of sodium alginate.
  • the biopolymer nanospheres containing NADH 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 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.
  • the granulation auxiliary material includes 16 parts of binder, 8 parts of microcrystalline cellulose, 10 parts of polyvinylpyrrolidone, 20 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 55 parts of biopolymer carrier and 8 parts of NADH, and the material of the biopolymer carrier is chitosan (CS).
  • the auxiliary material includes 20 parts of xanthan gum and 5 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, NADH 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, 4 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%.
  • FIGS. 4A and 4B Scanning electron microscopy tests were performed on the biopolymer nanospheres containing NADH prepared in Example 1, and the test results are shown in FIGS. 4A and 4B.
  • the biopolymer nanospheres have a honeycomb three-dimensional interpenetrating network structure.
  • 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.
  • NADH NADH at 2h, 4h, 6h and 8h respectively
  • the release rate and test results are shown in Table 2 and Figure 5.
  • the prepared preparation can release NADH active ingredients within 8 to 10 hours after oral administration. It stays in the gastric juice and releases the active ingredients 2 hours before the preparation, and stays in the small intestine and releases the active ingredients after 6 to 8 hours.
  • the above test results show that, under the immersion of the simulated gastric acid solution and the simulated colon solution, the active ingredient NADH in the prepared tablet can be slowly released into the 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 NADH 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 NADH is protected and its exposure to light or
  • the problem of easy decomposition after oxygen prolongs the preservation time of NADH active ingredients and reduces the difficulty of preservation.
  • the biopolymer nanospheres of the present invention most of the NADH 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 NADH active ingredients, so that the NADH loaded between the network structures is protected, and the problem that NADH is rapidly decomposed by stomach acid and cannot be fully utilized is solved.
  • Is a polymer carrier with intestinal sustained-release effect, and provides an ideal drug carrier for NADH to treat diseases such as Parkinson's disease, Alzheimer's disease, depression and cancer. By slowly releasing the active ingredients of NADH 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 three-dimensional interpenetrating fiber network, which is easy to load NADH in the network Be protected.
  • chitosan is a natural polymer material with good biofunctionality and compatibility, safety and microbial degradation, and because of its positive charge, it also has a bacteriostatic effect; konjac glucomannan Sugar is a natural high-molecular soluble dietary fiber with high viscosity, high water absorption and fast expansion. Due to its special glycosidic bond structure, it is also immunogenic.
  • 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 NADH 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 oxidation resistance, solves the problem of NADH decomposing by light and oxygen, and prolongs the preservation time of NADH; by grinding NADH raw materials After sieving, NADH is ground to a particle size of tens of nanometers, which makes it easier for NADH to enter the three-dimensional interpenetrating network structure of biopolymer materials and be protected.
  • the biopolymer nanospheres described in the present invention can be applied to the preparation of tablets, granules, capsules or soft capsules.
  • the NADH is protected from the network by biopolymer carriers In the structure, it is re-made into a pharmaceutical dosage form, which prevents the problem that NADH in the dosage form is decomposed by gastric juice and cannot be absorbed by the human body.
  • soft capsules disperse NADH-containing biopolymer nanospheres in the oil phase, which isolates the contact of NADH with air and water, further solves the problem of easy decomposition of NADH, and has a longer shelf life.

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Abstract

La présente invention concerne une nanosphère biologique de poids moléculaire élevé contenant du NADH qui comprend un support biologique de poids moléculaire élevé et du NADH dispersé sur le support biologique de poids moléculaire élevé. Le support biologique de poids moléculaire élevé est un polymère fibreux de poids moléculaire élevé, sa structure fibreuse constitue une structure de réseau interpénétrant tridimensionnel, offrant ainsi une protection pour le NADH, résolvant son problème qui est d'être susceptible à la décomposition lors d'une exposition à la lumière ou à l'oxygène, prolongeant le temps de conservation du composant actif du NADH et réduisant la difficulté de conservation. L'invention concerne également un procédé de préparation de la nanosphère biologique de poids moléculaire élevé. Un matériau biologique de poids moléculaire élevé d'une longueur de chaîne appropriée acquise par modification physique permet de former facilement des particules sphériques, constitue une structure de réseau interpénétrant tridimensionnel en nid d'abeilles, et favorise le chargement des micromolécules de NADH sur les surfaces interne et externe de la structure de réseau. La nanosphère biologique de poids moléculaire élevé peut être utilisée dans l'élaboration de préparations telles que des comprimés, des granules, des capsules ou des capsules molles pour servir de médicament thérapeutique/alicament fonctionnel pour la santé du corps humain ou pour animaux de compagnie.
PCT/CN2019/074220 2018-12-03 2019-01-31 Nanosphère biologique de poids moléculaire élevé contenant du nadh, son procédé de préparation et ses applications WO2020113812A1 (fr)

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CN109908089A (zh) * 2019-03-27 2019-06-21 泓博元生命科技（深圳）有限公司 含nadh或nadph的纳米微球及其制备方法与应用
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CN110354770B (zh) * 2019-07-23 2022-10-04 中国石油大学(华东) 一种人工光合微反应器及制备方法
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CN112807280B (zh) * 2021-01-07 2023-02-03 钇澜杉合成生物技术(北京)有限公司 多糖类生物高分子聚合物包覆nmn、nadh的制备工艺及其应用
CN113040311A (zh) * 2021-03-16 2021-06-29 江西省华宝孔雀食品科技发展有限公司 一种pH缓释型固体微胶囊及其制备方法
CN113713082B (zh) * 2021-08-27 2023-07-18 福建医科大学 一种用于阿尔茨海默症的纳米自噬诱导剂及其制备方法与应用

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