CN109646423A - Boiomacromolecule nanosphere containing NADH and the preparation method and application thereof - Google Patents

Boiomacromolecule nanosphere containing NADH and the preparation method and application thereof Download PDF

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Publication number
CN109646423A
CN109646423A CN201811465156.1A CN201811465156A CN109646423A CN 109646423 A CN109646423 A CN 109646423A CN 201811465156 A CN201811465156 A CN 201811465156A CN 109646423 A CN109646423 A CN 109646423A
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China
Prior art keywords
boiomacromolecule
nadh
nanosphere
carrier
parts
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Chinese (zh)
Inventor
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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Hongbo Yuan Technology (shenzhen) Ltd Life
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Hongbo Yuan Technology (shenzhen) Ltd Life
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Priority to CN201811465156.1A priority Critical patent/CN109646423A/en
Priority to PCT/CN2019/074220 priority patent/WO2020113812A1/en
Publication of CN109646423A publication Critical patent/CN109646423A/en
Pending legal-status Critical Current

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate 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
    • A61K9/146Intimate 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
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, 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
    • A23L29/00Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/30Foods 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
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, 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
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, 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
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21Addition of substantially indigestible substances, e.g. dietary fibres
    • A23L33/25Synthetic polymers, e.g. vinylic or acrylic polymers
    • A23L33/26Polyol polyesters, e.g. sucrose polyesters; Synthetic sugar polymers, e.g. polydextrose
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23PSHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00Shaping or working of foodstuffs characterised by the products
    • A23P10/20Agglomerating; Granulating; Tabletting
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23PSHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00Shaping or working of foodstuffs characterised by the products
    • A23P10/20Agglomerating; Granulating; Tabletting
    • A23P10/28Tabletting; Making food bars by compression of a dry powdered mixture
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23PSHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00Shaping or working of foodstuffs characterised by the products
    • A23P10/30Encapsulation of particles, e.g. foodstuff additives
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23PSHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00Shaping or working of foodstuffs characterised by the products
    • A23P10/30Encapsulation of particles, e.g. foodstuff additives
    • A23P10/35Encapsulation of particles, e.g. foodstuff additives with oils, lipids, monoglycerides or diglycerides
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23PSHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P20/00Coating of foodstuffs; Coatings therefor; Making laminated, multi-layered, stuffed or hollow foodstuffs
    • A23P20/20Making of laminated, multi-layered, stuffed or hollow foodstuffs, e.g. by wrapping in preformed edible dough sheets or in edible food containers
    • A23P20/25Filling or stuffing cored food pieces, e.g. combined with coring or making cavities
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/51Nanocapsules; Nanoparticles
    • A61K9/5107Excipients; Inactive ingredients
    • A61K9/513Organic macromolecular compounds; Dendrimers
    • A61K9/5161Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/24Antidepressants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23VINDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00Food compositions, function of food ingredients or processes for food or foodstuffs

Abstract

The invention discloses a kind of boiomacromolecule nanosphere containing NADH comprising boiomacromolecule carrier and the NADH being scattered on the boiomacromolecule carrier.The boiomacromolecule carrier is macromolecular fibre condensate; its fiber skeleton passes through the arrangement modes such as disorderly arranged, cross arrangement, curling arrangement; constitute three-dimensional interpenetrating polymer network structure; so that NADH is protected; it solves the problems, such as labile after it meets light or oxygen, extends the holding time of NADH effective component, reduces preservation difficulty.The invention also discloses the preparation processes of nanosphere, and by obtaining the bioabsorbable polymer material of medium-chain after physical modification, easily formation spherical particle, composition honeycomb three-dimensional interpenetrating polymer network structure are conducive to NADH small molecule and are carried on network structure surfaces externally and internally.Nanosphere can be used for preparing the preparations such as tablet, particle, capsule or soft capsule, as body-care or pet treat drug/functional food.

Description

Boiomacromolecule nanosphere containing NADH and the preparation method and application thereof
Technical field
The invention belongs to health product technical field, relate in particular to a kind of boiomacromolecule nanosphere containing NADH and Preparation method and application.
Background technique
The reduction-state of nicotinamide adenine dinucleotide (NADH) is a kind of coenzyme for transmitting proton, also referred to as reduced coenzyme I, during active somatic cell hundreds and thousands of a metabolic responses, NADH has redox active, in sugared ferment as electron donor Important Electron Transfer is played during solution, citrate cycle and photosynthesis etc..In vivo, NADH takes part in dimension Process, the generation process of atriphos (ATP) derived from raw element, and be the auxiliary of identified more than 250 kinds of dehydrogenases out Enzyme maintains cell growth, differentiation and energetic supersession.
NADH is considered to have the substance and without side-effects for increasingly increasing physical and intellectual performance effect, can be used for The drug improved health conditions with quality of life, clinical research show that parenteral administration NADH presses down treatment Parkinson's disease and severe Strongly fragrant disease has positive effect.NADH can promote parkinsonism, the cognitive ability of Alzheimer's and locomitivity, Yi Jihuan Tired, drowsiness, pigmentosa fatigue syndrome is solved, user's vigor and power are enhanced.
The middle of last century, successful treatment parkinsonism, alzheimer's disease etc. are various by way of infusion by NADH The nervous system disease and Delayed onset are dull-witted, but NADH medical fluid unstable chemcial property, instant need to match, so while this The center of gravity of biomolecule activates and has obtained determination before stimulation characteristic 50 years, but since its is highly sensitive (non-to light and oxygen It is often sensitive) and unstable feature, so that it is not used widely always.And divided immediately after being contacted due to NADH with gastric acid Solution leads to not take orally.
Summary of the invention
For this purpose, technical problem to be solved by the present invention lies in NADH unstable chemcial property, be difficult to store, can not mouth Clothes, to propose a kind of boiomacromolecule containing NADH for improving stability, being easy to save, is orally available, can be mass-produced Nanosphere and the preparation method and application thereof.
In order to solve the above technical problems, the technical solution of the present invention is as follows:
The present invention provides a kind of boiomacromolecule nanosphere containing NADH comprising boiomacromolecule carrier and is scattered in institute State the NADH on boiomacromolecule carrier.
Preferably, the boiomacromolecule carrier is in three-dimensional net structure, the average grain of the boiomacromolecule carrier Diameter is 200-1000nm.
Preferably, the boiomacromolecule carrier be chitosan and/or konjaku glucomannan,
Preferably, the konjaku glucomannan is konjaku glucomannan, quaternized konjaku glucomannan, carboxy methyl konjaku Portugal At least one of sweet glycan, deacetylated konjaku glucomannan.
Preferably, in parts by weight, the nanosphere includes 1-20 parts of NADH, 20-80 parts of bioabsorbable polymer materials,
Preferably, the nanosphere further includes auxiliary material, the auxiliary material in parts by weight, including 0.05-30 parts of sodium alginates And/or 0.05-30 parts of xanthan gum.
Preferably, the average grain diameter of the boiomacromolecule nanosphere containing NADH is 500-1000nm.
The present invention also provides a kind of methods for preparing the boiomacromolecule nanosphere containing NADH comprising following step It is rapid:
S1, by biopolymer feedstock and xanthan gum and/or sodium alginate mixed grinding, carry out physical modification, given birth to Object macromolecule carrier;
S2, grinding NADH raw material are simultaneously sieved, and obtain NADH;
S3, the NADH, boiomacromolecule carrier are mixed and stirred for get the boiomacromolecule nanosphere containing NADH.
The present invention also provides the boiomacromolecule nanospheres described in one kind containing NADH in preparation prevention and treatment inferior health, the medicine of tumour Application in object and/or functional food.
The present invention also provides a kind of pharmaceutical preparations, and NADH is contained described in the claim 1-5 any one comprising effective dose Boiomacromolecule nanosphere and pharmaceutically acceptable auxiliary material;
Preferably, the pharmaceutical preparation be selected from tablet, capsule, granule, injection, tincture, suppository, patch, pill, One of syrup, mixture, powder, lotion, film, dripping pill;
Preferably, the pharmaceutical preparation is capsule, the capsule includes hard capsule and soft capsule.
The present invention also provides a kind of methods for preparing the pharmaceutical preparation comprising the method for preparing particle:
A, granulation auxiliary material is added in the boiomacromolecule nanosphere to described containing NADH and is stirred;
B, the particle wet feed that uniform particle diameter is made is sieved;
C, the particle wet feed is dried to get particle;
The preparation of the heretofore described boiomacromolecule nanosphere containing NADH can carry out simultaneously with the preparation of dosage form, That is, it will be appreciated by those skilled in the art that, when NADH is mixed with the boiomacromolecule carrier, it is auxiliary that the granulation can be added Material is stirred together for, and then the particle containing NADH is directly made.
Preferably, including by particle tabletting is carried out, tablet is made;
Preferably, including by it is particles filled enter capsule shells in, capsule is made;
Preferably, including by particle with edible oil it mixes, is filled in soft capsule shell, soft capsule is made.
Preferably, the granulation auxiliary material is microcrystalline cellulose, polyvinylpyrrolidone, sodium bicarbonate, magnesium stearate, gathers At least one of calcium phosphate, wetting agent and adhesive.
The present invention also provides a kind of functional food, and it includes the boiomacromolecule nanospheres described in effective dose containing NADH With acceptable auxiliary material.
The above technical solution of the present invention has the following advantages over the prior art:
(1) the boiomacromolecule nanosphere of the present invention containing NADH comprising boiomacromolecule carrier and be scattered in NADH on the boiomacromolecule carrier.The boiomacromolecule carrier is macromolecular fibre condensate, and fiber skeleton is logical The arrangement modes such as disorderly arranged, cross arrangement, curling arrangement are crossed, three-dimensional interpenetrating polymer network structure are constituted, so that NADH is obtained Protection, solves the problems, such as labile after it meets light or oxygen, extends the holding time of NADH effective component, reduces preservation Difficulty.
(2) in the boiomacromolecule nanosphere of the present invention containing NADH, most of NADH is scattered in boiomacromolecule The inside of the three-dimensional interpenetrating polymer network of carrier, small part are carried on boiomacromolecule carrier outer surface.This three-dimensional interpenetrating polymer network knot The boiomacromolecule carrier of structure has both bioactivity and loads the effect of NADH effective component, makes to be carried between network structure NADH is protected, and solves the problems, such as that NADH meets gastric acid fast decoupled, is unable to give full play effectiveness, is a kind of slow with enteron aisle The macromolecule carrier of effect is released, the diseases such as parkinsonism, Alzheimer's disease, depression, cancer is treated for NADH and provides one The ideal pharmaceutical carrier of kind.It repairs DNA, further may be used also by sustained release NADH effective component, activation DNA repair enzyme With the generation of pre- anti-cancer.
(3) boiomacromolecule carrier of the present invention be chitosan (also known as CS) and/or konjaku glucomannan (also known as KGM), chitosan, konjaku glucomannan can form three-dimensional interpenetrating network of fibers, and being easy to, which is carried on NADH in network, is protected Shield.In addition, chitosan is a kind of natural macromolecular material, there is good biological functionality and compatibility, safety and micro- life Object degradability, and since itself has positive electricity, also have the function of antibacterial;A kind of natural macromolecule of konjaku glucomannan is solvable Property dietary fiber, viscosity is high, water suction is more, expansion is fast, due to special glucosides bond structure, also with immunogenicity.
(4) technique of the boiomacromolecule nanosphere described in preparation of the present invention containing NADH prepares physics first and changes Property boiomacromolecule carrier, by by biopolymer feedstock and xanthan gum and/or sodium alginate mixed grinding, will biology it is high The truncation of molecule long-chain is the strand of moderate length.Bioabsorbable polymer material medium-chain after physical modification, is more likely formed ball Shape particle constitutes honeycomb three-dimensional interpenetrating polymer network structure, so that being conducive to NADH small molecule is carried on network structure surfaces externally and internally. In addition, outer surface forms the structure of similar film by the boiomacromolecule carrier of physical modification, have waterproof anti-oxidation Effect solves the problems, such as that NADH meets light and oxygen solution, extends the NADH holding time;At grinding NADH raw material and sieving Reason, it is tens nanometers that NADH, which is ground to partial size, is easier to the three-dimensional interpenetrating polymer network structure for making NADH enter bioabsorbable polymer material In to being protected.
(5) the boiomacromolecule nanosphere of the present invention containing NADH can be applied to prepare tablet, granule, capsule or Soft capsule makes NADH be protected in network by boiomacromolecule carrier first by boiomacromolecule nanosphere of the preparation containing NADH In structure, then it is made as pharmaceutical dosage form, it is therefore prevented that the problem of NADH is decomposed, can not be absorbed by the body by gastric juice in dosage form.It is above-mentioned In dosage form, soft capsule disperses the boiomacromolecule nanosphere containing NADH in oily phase, has completely cut off NADH and air and water Contact, further solves the labile problem of NADH, has the longer shelf-life.
Detailed description of the invention
In order to make the content of the present invention more clearly understood, it below according to specific embodiments of the present invention and combines Attached drawing, the present invention is described in further detail, wherein
Fig. 1 is the XRD test result of the boiomacromolecule nanosphere under different NADH contents containing NADH;
Fig. 2 is the scanning electron microscope (SEM) photograph of the boiomacromolecule nanosphere described in the embodiment of the present invention 1 containing NADH;
Fig. 3 is the scanning electron microscope (SEM) photograph of the boiomacromolecule nanosphere described in the embodiment of the present invention 1 containing NADH;
Fig. 4 is that the boiomacromolecule nanosphere described in the embodiment of the present invention 2 containing NADH is made after tablet in simulation hydrochloric acid The release rate tendency chart of effective component after solution and simulation colon solution impregnate;
Fig. 5 is to tie after tablet is made in the boiomacromolecule nanosphere containing NADH of the embodiment of the present invention 2 in simulation The release rate tendency chart of effective component after enteric liquid impregnates.
Specific embodiment
Embodiment 1
The present embodiment provides a kind of boiomacromolecule nanosphere containing NADH, in parts by weight, including 20 parts of biologies are high Molecular vehicle and 1 part of NADH, the NADH are scattered on boiomacromolecule carrier, and the average grain diameter of boiomacromolecule carrier is 200-1000nm, the average grain diameter of the boiomacromolecule nanosphere containing NADH are 500-1000nm.In the present embodiment, the biology The material of macromolecule carrier is konjaku glucomannan (KGM), and KGM is natural polymer soluble dietary fiber, which is in bee Nest shape three-dimensional interpenetrating polymer network structure, the mesh size of network structure are tens to thousands of nanometers, and NADH is entered and born by mesh It is loaded in KGM network of fibers surface.The boiomacromolecule nanosphere further includes auxiliary material, the auxiliary material in parts by weight, including 0.05 part of sodium alginate.Sodium alginate is a kind of natural polysaccharide, and the ability with concentrate solution, formation gel and film forming can make Boiomacromolecule carrier outer surface forms a film structure, has the anti-oxidation effect of waterproof, avoids NADH and meets light or oxygen solution The problem of.
The present embodiment also provides a kind of method for preparing the boiomacromolecule nanosphere containing NADH comprising following step It is rapid:
S1, the boiomacromolecule carrier for preparing physical modification: by KGM and sodium alginate colloid mill mix grinding, make point of KGM Subchain length reduces, molecular weight reduces, formed honeycomb three-dimensional interpenetrating polymer network structure and it is agglomerating be average grain diameter partial size be 200- The nanosphere of 1000nm.
S2, grinding NADH raw material are simultaneously sieved, and obtain the NADH that average grain diameter is 10-100nm.
S3, NADH and the boiomacromolecule carrier that step S2 is obtained are mixed and stirred for uniformly to get containing NADH's Boiomacromolecule nanosphere.
It should be understood that the charging sequence between the NADH and the boiomacromolecule carrier is regardless of elder generation in the present invention Afterwards, it can be added with arbitrary charging sequence.
The present embodiment also provides a kind of pharmaceutical preparation, and the pharmaceutical preparation includes the biological high score containing NADH of effective dose Sub- nanosphere and pharmaceutically acceptable auxiliary material, the pharmaceutical preparation can for tablet, capsule, granule, injection, tincture, One of suppository, patch, pill, syrup, mixture, powder, lotion, film, dripping pill, in the present embodiment, the drug system Agent is particle, and the particle is prepared via a method which:
A, granulation auxiliary material is added in the boiomacromolecule nanosphere of Xiang Han NADH and is stirred, and the granulation auxiliary material includes 10 parts Wetting agent, 5 parts of adhesives, wherein the wetting agent is at least one of the second alcohol and water that volumetric concentration is 70%, adhesive For the pregelatinized starch of mass concentration 5-20%, mass concentration be 10-15% starch slurry, mass concentration be 10% hydroxypropyl first At least one of cellulose solution, in the present embodiment, wetting agent is ethyl alcohol, and adhesive is the starch slurry of mass concentration 10%.
B, it is pelletized with medium size steel wet sieving diameter, i.e., the material for having weighed weight is placed in that screen size is successively decreased from inside to outside one Bushing screen is online, and material stays in each layer compass screen surface according to granular size respectively, obtains particle wet feed.
C, wet feed is dried, is dried in vacuo 0.5-24h at 10-50 DEG C to get the boiomacromolecule nanosphere containing NADH Particle, in the present embodiment, drying temperature is 40 DEG C, time 3h.
It should be understood that in the present invention, between the boiomacromolecule nanosphere and the granulation auxiliary material containing NADH Charging sequence in no particular order, can be added with arbitrary charging sequence.
The preparation of the heretofore described boiomacromolecule nanosphere containing NADH can carry out simultaneously with the preparation of dosage form, That is, it will be appreciated by those skilled in the art that, when NADH is mixed with the boiomacromolecule carrier, it is total that granulation auxiliary material can be added With stirring.
Boiomacromolecule nanosphere described in the present embodiment containing NADH can also be used to prepare tablet, capsule or soft capsule, NADH effective component can be discharged after preparation oral obtained in 8-10h, before preparation 2h stopped in gastric juice and discharge effectively at Point, rear 6-8h is stopped in small intestine and is discharged effective component.The preparation can be used as prevention and treatment human-body sub-health, tumour drug or Pet treat drug.
The present embodiment also provides a kind of functional food comprising the boiomacromolecule nanometer containing NADH of effective dose Ball and appropriate acceptable auxiliary material, the auxiliary material includes pectin, fumaric acid, polydextrose, maltose, phosphatide, citric acid, hydroxypropyl At least one of base starch, lactic acid, D-sorbite, milk powder, maltodextrin.
Further, NADH raw material is prepared using following technique:
1, the crude extract or its pure enzyme of nicotinamide-nucleotide adenylyltransferase are extracted.
2, the crude extract or its pure enzyme of immobilization recombination nicotinamide-nucleotide adenylyltransferase.
3, it is catalyzed with immobilization recombination nicotinamide-nucleotide adenylyltransferase, with nicotinamide nucleotide and atriphos two Sodium (ATP) is that substrate prepares nicotinamide adenine dinucleotide.
Specific step is as follows:
Competence bacterial cell is converted by the plasmid pRSET bmj of niacinamide-containing nucleosides adenylyl transferase gene E.coliHB101 is cultivated 24 hours at 37 DEG C on Luriabroth (LB) plate (kanamycins containing 100mg/L).Inoculation Individually be cloned in 5 milliliters of LB liquid mediums (kanamycins containing 100mg/L) and in 30 DEG C culture 20-24 hours.Centrifugation is received Collect thallus, and is suspended in 1 milliliter of 100mM Tris hydrochloride buffer (pH7.5).Then ultrasonic treatment bacterial cell is used, from The heart (10 DEG C, 17800g, 10 minutes) simultaneously collects supernatant, as thick leach protein (or crude extract).The nicotinamide riboside of recombination Adenylyl transferase thick leach protein is heat-treated 10 minutes through 70 DEG C, is centrifuged (10 DEG C, 17800g, 10 minutes) and is collected supernatant, As partially purified albumen.
Nicotinamide-nucleotide adenylyltransferase immobilization: take nicotinamide-nucleotide adenylyltransferase thick leach protein or part pure The albumen of change is diluted to protein content 5- with enzyme buffer liquid (0.02MTris HCl/0.001M EDTA, pH7.0 solution) is washed 10mg/ml.Enzyme dilution and PB solution (2.0mol/L potassium dihydrogen phosphate, pH7.5) are mixed in equal volume, epoxy type is added and fixes Change zymophore LX 3000 (10 milligrams of enzymes/gram carrier), is reacted 20 hours for 25 DEG C in shaking table (revolving speed 100rpm).Reaction is completed Sock filtration is used afterwards, is cleaned 5-6 times with enzyme buffer liquid is washed, is obtained immobilization nicotinamide-nucleotide adenylyltransferase.
Nicotinamide adenine dinucleotide is prepared with immobilization nicotinamide-nucleotide adenylyltransferase: preparing substrate solution: The trinosin (ATP) of nicotinamide nucleotide, 10mM containing 5mM, 100mMTris hydrochloride buffer and final concentration of The MgCl of 10mM2, adjust pH to 7.5.1 milliliter of substrate solution is taken, 0.05 gram of immobilization nicotinamide riboside adenylyl is then added and turns Enzyme is moved, reaction 2-20 hours is carried out in 37 DEG C.Centrifugation (10 DEG C, 17800g, 15 minutes) simultaneously collects supernatant.Pass through high pressure liquid phase The content of nicotinamide adenine dinucleotide in chromatography (HPLC) measurement gained supernatant.The result shows that nicotinamide nucleotide turns The conversion ratio for turning to nicotinamide adenine dinucleotide is more than 80%.
Embodiment 2
The present embodiment provides a kind of boiomacromolecule nanosphere containing NADH, in parts by weight, including 80 parts of biologies are high Molecular vehicle and 20 parts of NADH, the NADH are scattered on boiomacromolecule carrier, and the average grain diameter of boiomacromolecule carrier is 200-1000nm, the average grain diameter of the boiomacromolecule nanosphere containing NADH are 500-1000nm.In the present embodiment, the life The material of object macromolecule carrier is the mixing of quaternized konjaku glucomannan (QKGM) and Carboxymethyl Konjac Glucomannan (CKGM) Object, the two mass ratio are 1:1, and above-mentioned Modified K GM is natural polymer soluble dietary fiber, and the fiber is three-dimensional mutually in honeycomb Network structure is worn, the mesh size of network structure is tens to thousands of nanometers, and NADH is entered by mesh and is carried on KGM fiber Network surface.
The boiomacromolecule nanosphere further includes auxiliary material, in the present embodiment, the auxiliary material in parts by weight, including 30 Part sodium alginate.
The preparation method preparation of embodiment 1 can be used in boiomacromolecule nanosphere described in the present embodiment containing NADH, Difference is that boiomacromolecule carrier is quaternized konjaku glucomannan (QKGM) and Carboxymethyl Konjac Glucomannan (CKGM) Mixture.
The ammonium konjaku glucomannan (QKGM) and Carboxymethyl Konjac Glucomannan (CKGM) are by konjaku glucomannan (KGM) it is made through carboxy methylation, quaternary ammoniated processing.It can also be sweet by quaternized konjaku glucomannan (QKGM) and carboxy methyl konjaku Portugal The NaOH of the HCl or 0.1-1mol/L of glycan (CKGM) and concentration 0.1-1mol/L are stirred together for 2-10h, reduce konjak portuguese gansu polyose The molecular weight of sugar facilitates subsequent physical modified.
The present embodiment also provides a kind of pharmaceutical preparation, and the pharmaceutical preparation includes the biological high score containing NADH of effective dose Sub- nanosphere and pharmaceutically acceptable auxiliary material, in the present embodiment, the pharmaceutical preparation is tablet, and the tablet passes through such as lower section Method preparation: it is pelletized using the method for granulation described in embodiment 1, particle obtained is handled with tabletting machine then, is passed through The parameter and pressure for adjusting compression mold, can be prepared by the tablet of aimed dia, thickness and hardness.The method of granulating of the present embodiment The difference from embodiment 1 is that: granulation auxiliary material is different, and in the present embodiment, granulation auxiliary material includes 40 parts of adhesives, 30 parts of stearic acid Magnesium and 30 parts of microcrystalline celluloses, wherein described adhesive is the pregelatinized starch of mass concentration 5% and mass concentration is 10% Hydroxypropyl methylcellulose solution mixture.
Pregelatinized starch in granulation auxiliary material, not only has good disintegration, adhesive effect, also can obviously improve tabletting Hardness, disintegration and surface brightness, it is often more important that improve dissolution rate, reduce granulation difficulty, improve particle granulating Property and compressibility, the tablet hardness of compacting is high, embrittlement degree is small, surface is smooth.Hydroxypropyl methylcellulose is hydroxypropyl and methoxyl group The displacement group of the derivative of cellulose mixing ether, intramolecular is ethers, tablet is used for, mainly as adhesive and disintegration Agent improves disintegration, dissolution rate increases.Microcrystalline cellulose mobility and compressibility are good, have both bonding, lubricate and help disintegration Can, with drug without interaction, the bright and clean beautiful, easy disintegrating of tabletting shape can be made.
The present embodiment also provides a kind of functional food comprising the boiomacromolecule nanometer containing NADH of effective dose Ball and appropriate acceptable auxiliary material, the auxiliary material includes honey, cornstarch, corn oil, sesame oil, sucrose, vitamin C, dimension At least one of raw element E, xylitol, gelatin.
Embodiment 3
The present embodiment provides a kind of boiomacromolecule nanosphere containing NADH, in parts by weight, including 45 parts of biologies are high Molecular vehicle and 5 parts of NADH, the NADH are scattered on boiomacromolecule carrier, and the average grain diameter of boiomacromolecule carrier is 200-1000nm, the average grain diameter of the boiomacromolecule nanosphere containing NADH are 500-1000nm.In the present embodiment, the life The material of object macromolecule carrier is deacetylated konjaku glucomannan (da-KGM), and above-mentioned Modified K GM is that natural polymer is soluble Dietary fiber, the fiber are in honeycomb three-dimensional interpenetrating polymer network structure, and the mesh size of network structure is tens to thousands of nanometers, NADH is entered by mesh and is carried on KGM network of fibers surface.
The boiomacromolecule nanosphere further includes auxiliary material, in the present embodiment, the auxiliary material in parts by weight, including 15 Part sodium alginate.
The preparation method preparation of embodiment 1 can be used in boiomacromolecule nanosphere described in the present embodiment containing NADH, Difference is that boiomacromolecule carrier is deacetylated konjaku glucomannan (da-KGM), the deacetylated konjaku glucomannan (da-KGM) it is made by KGM through deacetylated processing.Further include before step S1 by deacetylated konjaku glucomannan (da-KGM) with The NaOH of the HCl or 0.1-1mol/L of concentration 0.1-1mol/L are stirred together for 2-10h, reduce the molecular weight of konjaku glucomannan, Facilitate subsequent physical modified.
The present embodiment also provides a kind of pharmaceutical preparation, and the pharmaceutical preparation includes the biological high score containing NADH of effective dose Sub- nanosphere and pharmaceutically acceptable auxiliary material, in the present embodiment, the pharmaceutical preparation is capsule, and the capsule is by such as Lower section method preparation: using granulation described in embodiment 1 method pelletize, after granulation, as the method for quantitative filling will made from Particle is fitted into commercially available edibility hard capsule shell to arrive capsule preparations.The method of granulating of the present embodiment and the area of embodiment 1 Be not: granulation auxiliary material is different, in the present embodiment, pelletizes auxiliary material in parts by weight, including 20 parts of adhesives, 0.5 part of stearic acid Magnesium and 0.5 part of microcrystalline cellulose, 1 part of polyvinylpyrrolidone, 2 parts of sodium bicarbonates, 20 parts of wetting agents, wherein the wetting agent For the ethyl alcohol of volumetric concentration 70%, described adhesive is the starch slurry of mass concentration 10%.
For microcrystalline cellulose in auxiliary material as filler and disintegrating agent, polyvinylpyrrolidone plays protection drug and dispersion Effect, facilitate the release of drug.
Embodiment 4
The present embodiment provides a kind of boiomacromolecule nanosphere containing NADH, in parts by weight, including 60 parts of biologies are high Molecular vehicle and 5.2 parts of NADH, the NADH are scattered on boiomacromolecule carrier, and the average grain diameter of boiomacromolecule carrier is 200-1000nm, the average grain diameter of the boiomacromolecule nanosphere containing NADH are 500-1000nm.In the present embodiment, the life The material of object macromolecule carrier is konjaku glucomannan (KGM), and KGM is natural polymer soluble dietary fiber, which is in Honeycomb three-dimensional interpenetrating polymer network structure, the mesh size of network structure are tens to thousands of nanometers, and NADH is entered simultaneously by mesh It is carried on KGM network of fibers surface.
The boiomacromolecule nanosphere further includes auxiliary material, in the present embodiment, the auxiliary material in parts by weight, including 30 Part xanthan gum.
The preparation method preparation of embodiment 1 can be used in boiomacromolecule nanosphere described in the present embodiment containing NADH, Difference is, further includes that the NaOH of the HCl or 0.1-1mol/L by KGM Yu concentration 0.1-1mol/L is stirred together for 2- before step S1 10h reduces the molecular weight of konjaku glucomannan, facilitates subsequent physical modified.
The present embodiment also provides a kind of pharmaceutical preparation, and the pharmaceutical preparation includes the biological high score containing NADH of effective dose Sub- nanosphere and pharmaceutically acceptable auxiliary material, in the present embodiment, the pharmaceutical preparation is soft capsule, and the soft capsule is logical It crosses following method preparation: being pelletized using the method for granulation described in embodiment 1, after granulation, by particle obtained and proper amount of edible Oil, biosurfactant mixing, then encapsulate into commercially available soft capsule shell, obtain soft capsule preparation, the edible oil It can be olive oil, sesame oil, soybean oil, corn oil, camellia oil, grape seed oil etc..The method of granulating and embodiment 1 of the present embodiment Difference be: granulation auxiliary material is different, in the present embodiment, granulation auxiliary material in parts by weight, including 16 parts of adhesives, 2 parts of tristearin Sour magnesium, 1 part of calcium polyphosphate, 15 parts of wetting agents, wherein the wetting agent is the ethyl alcohol of volumetric concentration 70%, and described adhesive is The hydroxypropyl methylcellulose solution of mass concentration 10%.
Embodiment 5
The present embodiment provides a kind of boiomacromolecule nanosphere containing NADH, in parts by weight, including 40 parts of biologies are high Molecular vehicle and 12 parts of NADH, the NADH are scattered on boiomacromolecule carrier, and the average grain diameter of boiomacromolecule carrier is 200-1000nm, the average grain diameter of the boiomacromolecule nanosphere containing NADH are 500-1000nm.In the present embodiment, the biology The material of macromolecule carrier is konjaku glucomannan (KGM), and KGM is natural polymer soluble dietary fiber, which is in bee Nest shape three-dimensional interpenetrating polymer network structure, the mesh size of network structure are tens to thousands of nanometers, and NADH is entered and born by mesh It is loaded in KGM network of fibers surface.
The boiomacromolecule nanosphere further includes auxiliary material, in the present embodiment, the auxiliary material in parts by weight, including 0.05 part of xanthan gum, 13 parts of sodium alginates.
The preparation method preparation of embodiment 1 can be used in boiomacromolecule nanosphere described in the present embodiment containing NADH, Difference is, further includes that the NaOH of the HCl or 0.1-1mol/L by KGM Yu concentration 0.1-1mol/L is stirred together for 2- before step S1 10h reduces the molecular weight of konjaku glucomannan, facilitates subsequent physical modified.
The present embodiment also provides a kind of pharmaceutical preparation, and the pharmaceutical preparation includes the biological high score containing NADH of effective dose Sub- nanosphere and pharmaceutically acceptable auxiliary material, in the present embodiment, the pharmaceutical preparation is granule, and the granule passes through reality Apply the preparation of method described in example 1, difference is: granulation auxiliary material is different, in the present embodiment, pelletizes auxiliary material in parts by weight, including 5 Part adhesive, 12 parts of microcrystalline celluloses, 15 parts of wetting agents, wherein the wetting agent is the second alcohol and water of volumetric concentration 70% Mixture, described adhesive are the pregelatinized starch of mass concentration 15%.
Embodiment 6
The present embodiment provides a kind of boiomacromolecule nanosphere containing NADH, in parts by weight, including 70 parts of biologies are high Molecular vehicle and 15 parts of NADH, the NADH are scattered on boiomacromolecule carrier, and the average grain diameter of boiomacromolecule carrier is 200-1000nm, the average grain diameter of the boiomacromolecule nanosphere containing NADH are 500-1000nm.In the present embodiment, the biology The material of macromolecule carrier is chitosan (CS), and CS is natural macromolecular material, which has honeycomb three-dimensional interpenetrating polymer network Structure, the mesh size of network structure are tens to thousands of nanometers, and NADH is entered by mesh and is carried on chitosan network table Face.
The boiomacromolecule nanosphere further includes auxiliary material, in the present embodiment, the auxiliary material in parts by weight, including 15 Part xanthan gum, 24 parts of sodium alginates.
The preparation method preparation of embodiment 1 can be used in boiomacromolecule nanosphere described in the present embodiment containing NADH, Difference is, further includes the chemical modification step that chitosan is carried out to quaternary ammoniated processing before step S1, reduces the molecule of chitosan Amount facilitates subsequent physical modified.
The present embodiment also provides a kind of pharmaceutical preparation, and the pharmaceutical preparation includes the biological high score containing NADH of effective dose Sub- nanosphere and pharmaceutically acceptable auxiliary material, in the present embodiment, the pharmaceutical preparation is tablet, and the tablet passes through such as lower section Method preparation: it is pelletized using the method for granulation described in embodiment 1, particle obtained is handled with tabletting machine then, is passed through The parameter and pressure for adjusting compression mold, can be prepared by the tablet of aimed dia, thickness and hardness, the method for granulating of the present embodiment The difference from embodiment 1 is that: granulation auxiliary material is different, in the present embodiment, pelletizes auxiliary material in parts by weight, including 16 parts of bondings Agent, 8 parts of microcrystalline celluloses, 10 parts of polyvinylpyrrolidones, 20 parts of sodium bicarbonates, 13 parts of wetting agents, wherein the wetting agent is The mixture of the second alcohol and water of volumetric concentration 70%, described adhesive are the starch slurry of mass concentration 10%.
Embodiment 7
The present embodiment provides a kind of boiomacromolecule nanosphere containing NADH, in parts by weight, including 55 parts of biologies are high Molecular vehicle and 8 parts of NADH, the NADH are scattered on boiomacromolecule carrier, and the average grain diameter of boiomacromolecule carrier is 200-1000nm, the average grain diameter of the boiomacromolecule nanosphere containing NADH are 500-1000nm.In the present embodiment, the biology The material of macromolecule carrier is chitosan (CS), and CS is natural macromolecular material, which has honeycomb three-dimensional interpenetrating polymer network Structure, the mesh size of network structure are tens to thousands of nanometers, and NADH is entered by mesh and is carried on chitosan network table Face.
The boiomacromolecule nanosphere further includes auxiliary material, in the present embodiment, the auxiliary material in parts by weight, including 20 Part xanthan gum, 5 parts of sodium alginates.
The preparation method preparation of embodiment 1 can be used in boiomacromolecule nanosphere described in the present embodiment containing NADH, Difference is that boiomacromolecule carrier is chitosan.
The present embodiment also provides a kind of pharmaceutical preparation, and the pharmaceutical preparation includes the biological high score containing NADH of effective dose Sub- nanosphere and pharmaceutically acceptable auxiliary material, in the present embodiment, the pharmaceutical preparation is granule, and the granule passes through reality Apply the preparation of method described in example 1, difference is: granulation auxiliary material is different, in the present embodiment, pelletizes auxiliary material in parts by weight, including 8 Part adhesive, 6 parts of microcrystalline celluloses, 4 parts of polyvinylpyrrolidones, 5 parts of sodium bicarbonates, 10 parts of magnesium stearates, 10 parts of polyphosphoric acids Calcium, 15 parts of wetting agents, wherein the wetting agent is the mixture of the second alcohol and water of volumetric concentration 70%, and described adhesive is matter Measure the mixture of the starch slurry of concentration 10%, the pregelatinized starch of mass concentration 15%.
Experimental example
1, there is the life containing NADH of different NADH contents (0%, 8%, 10%) by X-ray diffraction method (XRD) detection Object high molecular nanometer sphere obtains XRD diffraction pattern as shown in Figure 1, it can be seen from the figure that the boiomacromolecule of unsupported NADH Carrier (blank microballoon) shows the diffraction broad peak (2 angles θ are the diffraction maximum at 18 ° and 22.5 °) of polysaccharide cellulose, load After NADH, newly there are multiple diffraction maximums, be the characteristic diffraction peak of NADH, and the nanosphere XRD diffraction maximum containing 10%NADH Intensity is high compared with the nanosphere containing 8%NADH, further demonstrates NADH and is successfully carried on boiomacromolecule carrier.
2, pass through the shape of the boiomacromolecule nanosphere described in the scanning electron microscope test embodiment of the present invention 1 containing NADH Looks, as a result as Figure 2-3, it is seen that bioabsorbable polymer material is in honeycomb three-dimensional interpenetrating polymer network structure.
3, tablet made from embodiment 2 is impregnated to 2h under conditions of simulation hydrochloric acid solution S GF pH=2 and then is being simulated 6h is impregnated under conditions of colon solution S CF pH=6.8, tests the release rate of the 2nd, 4,6,8h NADH respectively, test result is such as Shown in table 1 and Fig. 4.
Table 1
Time h Release rate %
0 0
2 1.12
4 20.72
6 50.24
8 90.33
Surplus 0.30
Total amount 90.63
4, tablet made from embodiment 2 is impregnated into 8h under conditions of simulating colon solution S CF pH=6.8, tested respectively The release rate of 2nd, 4,6,8hNADH, test result is as shown in table 2 and Fig. 5.
Table 2
Time h Release rate %
0 0
2 39.57
4 66.85
6 85.5
8 93.27
Surplus 2.10
Total amount 95.37
Above-mentioned test result shows in the case where simulation hydrochloric acid solution and simulation colon solution impregnate, effective in tablet obtained Ingredient NADH can be sustained into solution, be a kind of long-acting medicament.
Obviously, the above embodiments are merely examples for clarifying the description, and does not limit the embodiments.It is right For those of ordinary skill in the art, can also make on the basis of the above description it is other it is various forms of variation or It changes.There is no necessity and possibility to exhaust all the enbodiments.And it is extended from this it is obvious variation or It changes still within the protection scope of the invention.

Claims (10)

1. a kind of boiomacromolecule nanosphere containing NADH, which is characterized in that including boiomacromolecule carrier and be scattered in described NADH on boiomacromolecule carrier.
2. the boiomacromolecule nanosphere according to claim 1 containing NADH, which is characterized in that the boiomacromolecule carries Body is in three-dimensional net structure, and the average grain diameter of the boiomacromolecule carrier is 200-1000nm.
3. the boiomacromolecule nanosphere according to claim 1 containing NADH, which is characterized in that the boiomacromolecule carries Body be chitosan and/or konjaku glucomannan,
Preferably, the konjaku glucomannan is that konjaku glucomannan, quaternized konjaku glucomannan, carboxy methyl konjaku Portugal are sweet poly- At least one of sugared, deacetylated konjaku glucomannan.
4. the boiomacromolecule nanosphere according to claim 1 containing NADH, which is characterized in that in parts by weight, described Nanosphere includes 1-20 parts of NADH, 20-80 parts of boiomacromolecule carriers,
Preferably, the nanosphere further includes auxiliary material, the auxiliary material in parts by weight, including 0.05-30 parts of sodium alginates and/or 0.05-30 parts of xanthan gum.
5. the boiomacromolecule nanosphere according to claim 1 containing NADH, which is characterized in that the biology containing NADH The average grain diameter of high molecular nanometer sphere is 500-1000nm.
6. a kind of method for preparing the boiomacromolecule nanosphere as described in any one in claim 1-5 containing NADH, feature It is, includes the following steps:
S1, by biopolymer feedstock and xanthan gum and/or sodium alginate mixed grinding, carry out physical modification, obtain biological height Molecular vehicle;
S2, grinding NADH raw material are simultaneously sieved, and obtain NADH;
S3, the NADH, boiomacromolecule carrier are mixed and stirred for get the boiomacromolecule nanosphere containing NADH.
7. a kind of boiomacromolecule nanosphere as described in claim any one of 1-5 containing NADH is preparing prevention and treatment inferior health, is swelling The drug of tumor and/or the application in functional food.
8. a kind of pharmaceutical preparation, the boiomacromolecule containing NADH described in the claim 1-5 any one comprising effective dose is received Rice ball and pharmaceutically acceptable auxiliary material;
Preferably, the pharmaceutical preparation is selected from tablet, capsule, granule, injection, tincture, suppository, patch, pill, syrup One of agent, mixture, powder, lotion, film, dripping pill;
Preferably, the pharmaceutical preparation is capsule, and the capsule includes hard capsule and soft capsule.
9. a kind of method for preparing pharmaceutical preparation as claimed in claim 8, which is characterized in that the method including preparing particle:
A, granulation auxiliary material is added in the boiomacromolecule nanosphere to described containing NADH and is stirred;
B, the particle wet feed that uniform particle diameter is made is sieved;
C, the particle wet feed is dried to get particle;
Preferably, including by particle tabletting is carried out, tablet is made;
Preferably, including by it is particles filled enter capsule shells in, capsule is made;
Preferably, including by particle with edible oil it mixes, is filled in soft capsule shell, soft capsule is made.
Preferably, the granulation auxiliary material is microcrystalline cellulose, polyvinylpyrrolidone, sodium bicarbonate, magnesium stearate, polyphosphoric acid At least one of calcium, wetting agent and adhesive.
10. a kind of functional food, the boiomacromolecule containing NADH described in the claim 1-5 any one comprising effective dose is received Rice ball and acceptable auxiliary material.
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