CN108201543A - Application of the water-soluble fullerene structure in the drug for preparing treatment fatty liver - Google Patents
Application of the water-soluble fullerene structure in the drug for preparing treatment fatty liver Download PDFInfo
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- CN108201543A CN108201543A CN201710560609.8A CN201710560609A CN108201543A CN 108201543 A CN108201543 A CN 108201543A CN 201710560609 A CN201710560609 A CN 201710560609A CN 108201543 A CN108201543 A CN 108201543A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/44—Elemental carbon, e.g. charcoal, carbon black
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
The invention discloses a kind of application of water-soluble fullerene structure in the drug for preparing treatment fatty liver, also disclose a kind of pharmaceutical composition and method for treating fatty liver.In the present invention treat fatty liver active ingredient for water-soluble fullerene, water-soluble embedded metal fullerene, water-soluble fullerene and the composition of water-soluble embedded metal fullerene, the pharmaceutical ester of above three, above three officinal salt.The active ingredient water-soluble fullerene structure of the present invention can reduce fat bubble in liver, reduce blood fat, hence it is evident that improving liver function makes glutamic-pyruvic transaminase and glutamic-oxalacetic transaminease content tend to be normal, achievees the effect that efficiently to treat fatty liver；Active ingredient water-soluble fullerene structure can also adjust liver internal oxidition reduced level simultaneously.
Description
The present invention claims Beijing Fu Nakang Bioisystech Co., Ltd and Institute of Chemistry, Academia Sinica in 2016 12
Months 19 days it is being submitted to Patent Office of the People's Republic of China, application No. is CN201611180067.3, entitled " water-soluble fullerene structures
The priority of the Chinese patent application of application in the drug for preparing treatment fatty liver ", all the contents of the application are by drawing
With combination in the present invention.
Technical field
The present invention relates to field of medicaments, more particularly, to a kind of water-soluble fullerene structure in the medicine for preparing treatment fatty liver
Application in object.
Background technology
Fatty liver disease (i.e. fatty liver) be it is a kind of can fat accumulation be excessive in liver cell as caused by a variety of inducements
Lesion, while be also a kind of pathologic process in a variety of liver diseases evolutions, it is one of most common diffuse liver disease.Fat
The mechanism of fat liver is not yet completely clear and definite so far.Fatty liver shows as the especially triglycerides accumulation of liver inner lipid excessively, more than liver
The 5% of dirty weight；Or histologically more than 50% liver parenchyma fat, there is vacuole in liver cell more than half.
Fatty liver can be divided into alcoholic fatty liver, obesity fatty liver, hyperlipemia-fatty liver, diabetic keratopathy according to pathogenesis
Fatty liver, trophic disturbance fatty liver, Drug fatty liver and pregnancy fatty liver etc..Cholesterol fatty liver, phosphatide can be also divided into
Matter fatty liver and neutral fat fatty liver, wherein most common is the neutral fat fat that improper accumulation is formed in liver
Liver.
In recent years, it is various with the variation of our people's living and diet structure and the raising of medical imaging technology
Diagnosis of the fatty liver in China caused by inducement increases year by year.The health of the positive serious threat compatriots of fatty liver, becomes and is only second to
The second largest hepatopathy of virus hepatitis.If fatty liver is not treated timely, it is likely that be developing progressively steatohepatitis,
Liver fibrosis, hepatic sclerosis, latter stage hepatic failure or liver cancer.
Fullerene is another allotrope of the carbon in addition to graphite, diamond and agraphitic carbon.This kind of substance
Refer to the cage structure being made of carbon atom, the most molecule of content is C60, followed by C70、C84, secondly content is opposite
Less C76、C78、C82Deng.Carbon cage inside additionally, due to fullerene is cavity structure, therefore its internal cavities can embed difference
Atom, ion or cluster are referred to as embedded fullerene, such as La@C60, represent that La is embedded in C60Cage structure in ,@tables
Show at, vivid expresses embedded meaning.
The information for being disclosed in the background technology part is merely intended to increase the understanding of the general background to the present invention, without answering
When being considered as recognizing or imply that information composition has been the prior art well known to persons skilled in the art in any form.
Invention content
The purpose of the present invention is to provide a kind of water-soluble fullerene, water-soluble embedded metal fullerene, water solubilitys
Fullerene and the composition of water-soluble embedded metal fullerene, above three pharmaceutical ester or more three can medicine
Application of the salt in the drug for preparing treatment fatty liver.Another object of the present invention is to provide a kind of fatty liver for the treatment of
Pharmaceutical composition and method.The active ingredient water-soluble fullerene structure of the present invention can reduce liver index, reduce liver lactones
Fat steeps and fat content, reduces blood fat, hence it is evident that improving liver function makes glutamic-pyruvic transaminase and glutamic-oxalacetic transaminease content tend to be normal, reaches
To the effect of efficient treatment fatty liver；Active ingredient water-soluble fullerene structure can also adjust liver internal oxidition reductive water simultaneously
It is flat.
In order to realize purpose, the present invention provides following technical schemes：
A kind of water-soluble fullerene, water-soluble embedded metal fullerene, the water-soluble fullerene and the water
It is prepared by the pharmaceutical salt of the composition of the embedded metal fullerene of dissolubility, the pharmaceutical ester of above three or more three
Treat the application in the drug of fatty liver.
The present invention also provides a kind of method for treating fatty liver, including applying effective quantity to the subject with fatty liver
At least one active ingredient selected from the group below：Water-soluble fullerene, water-soluble embedded metal fullerene, the water solubility
The fullerene and composition of the water-soluble embedded metal fullerene, the pharmaceutical ester of above three and more than three
Pharmaceutical salt.
The present invention also provides a kind of pharmaceutical composition for treating fatty liver, including it is at least one it is selected from the group below effectively into
Point：Water-soluble fullerene, water-soluble embedded metal fullerene, the water-soluble fullerene and described water-soluble embedded
The composition of metal fullerene, the pharmaceutical ester of above three, above three officinal salt, described pharmaceutical composition also wraps
Include at least one of pharmaceutical carrier, pharmaceutical diluent and pharmaceutical excipient.
In another embodiment, the water-soluble fullerene is selected from down for above application, method or pharmaceutical composition
That organizes is one or more：(1) carbon cage outer surface is modified with the fullerene of hydrophilic radical；(2) carbon cage outer surface is by hydrophily biology
The fullerene of small molecule package；(3) fullerene loaded by the carrier material with biocompatibility；(4) it is self-assembly of
Water-soluble supramolecular system fullerene.
Above application, method or pharmaceutical composition in another embodiment, the water-soluble embedded metal fowler
Alkene is selected from the group below one or more：(1) carbon cage outer surface is modified with the embedded metal fullerene of hydrophilic radical；(2) outside carbon cage
The embedded metal fullerene that surface is wrapped up by hydrophily biological micromolecule；(3) it is loaded by the carrier material with biocompatibility
Embedded metal fullerene；(4) the water-soluble supramolecular system embedded metal fullerene being self-assembly of.
In another embodiment, the fullerene includes one or more for above application, method or pharmaceutical composition
General formula is C2mThe cage structure being made of carbon atom, 30≤m≤60, such as；C60, C70, C84Deng.
In another embodiment, the embedded metal fullerene includes M@for above application, method or pharmaceutical composition
C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2nAnd MxA3-xN@C2nIn it is one or more, wherein：M、A
It represents metallic element and M, A is selected from any one in lanthanide element, Sc and Y, 30≤n≤60,0≤x≤3, example
Such as：Gd@C82.N represents nitrogen, and C represents carbon, and S represents element sulphur, lanthanide element include La, Ce, Pr, Nd, Pm,
Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
In another embodiment, the hydrophilic radical includes hydroxyl, carboxylic for above application, method or pharmaceutical composition
It is one or more in base, sulfydryl, amino and water-soluble amino acids residue.
In another embodiment, the water-soluble amino acids residue refers to for above application, method or pharmaceutical composition
Water-soluble amino acids are modifying fullerene and/or during embedded metal fullerene, lose remaining after a part for amino acid molecular
Incomplete amino acid, i.e.,：Amino acid residue is a part for amino acid molecular, is incomplete amino acid.Lack amino
Any one of acid molecule part is all amino acid residue, such as：It loses the hydrogen in amino acid on amino, lose in amino acid
Hydrogen or hydroxyl on carboxyl etc..Optionally, the water-soluble amino acids residue is alanine residue, glycine residue, serine
At least one of residue, arginine residues, lysine residue and tianmenine residue.
Above application, method or pharmaceutical composition in another embodiment, the general formula of the water-soluble fullerene
For C2a(OH)b(Amino Acid)c, Amino Acid represent water-soluble amino acids residue；30≤a≤60, optional a for 30 or
35；0<b<50, optional 0<b<30, also optional b=13,20,22,24 etc.；0≤c<20, optional c=2-15, it is also optional
C=6.
Above application, method or pharmaceutical composition in another embodiment, the water-soluble embedded metal fowler
The general formula of alkene is M@C2d(OH)e(Amino Acid)f, Amino Acid represent water-soluble amino acids residue；M is selected from rare earth gold
Belong to, optional rare earth metal is Gd, La etc.；30≤d≤60, optional d are 41 or 30 or 35；0<e<50, optional 0<e<30,
Also optional e=13,20,22,24 etc.；0≤f<20, optional f=2-15, also optional f=6.
In another embodiment, the hydrophily biological micromolecule includes for above application, method or pharmaceutical composition
At least one of amino acid and peptide chain.
Above application, method or pharmaceutical composition in another embodiment, the carrier with biocompatibility
Material includes at least one of liposome and cell membrane carrier.
In another embodiment, the water-soluble fullerene is to pass through for above application, method or pharmaceutical composition
Water-soluble modified acquisition is carried out to raw material fullerene；The water-soluble embedded metal fullerene is by embedding gold to raw material
Belong to fullerene and carry out water-soluble modified acquisition.
Above application, method or pharmaceutical composition in another embodiment, the water-soluble modified method be with
Any one of lower method：(1) method of surface modification hydrophilic radical is generally anti-by solid-liquid or liquid liquid in the presence of alkali
It should realize, specially mix at least one of raw material fullerene and raw material embedded metal fullerene with hydrogen peroxide and aqueous slkali
And reacted, then washed with ethyl alcohol, it then dialyses, you can obtain water soluble hydroxy derivative corresponding with raw material.If it needs
Water-soluble amino derivative is obtained, the sodium hydroxide in above-mentioned steps is substituted for ammonium hydroxide.(2) side of physics cladding
Method can by least one of raw material fullerene and raw material embedded metal fullerene and polyethylene glycol, polyvinylpyrrolidone and
At least one of cyclodextrin, which mixes and carries out ball milling or ultrasound etc., can be obtained by the water solubility being wrapped by corresponding with raw material
Fullerene structure, such as the fullerene of coated with polyethylene glycol and/or the embedded metal fullerene of coated with polyethylene glycol, polyvinyl pyrrole
The fullerene of alkanone cladding and/or the embedded metal fullerene of polyvinylpyrrolidone cladding.(3) when water-soluble fullerene knot
When the number containing amino acid residue is not 0 in structure, include the following steps：(a) it is prepared using water-soluble amino acids and NaOH/KOH
(optional, the molar ratio of water-soluble amino acids and NaOH/KOH are 1 to water soluble amino acid-base solution:1-10, also optional is 1:
2 or 1:1-8；Optionally, the mass fraction of NaOH/KOH can be 10~50% in water soluble amino acid-base solution, also be optionally
14% or 10~30%)；(b) it is 1-1000 according to amino acid and raw material fullerene/raw material embedded metal fullerene molar ratio:1,
It is optionally 50-1000：1,100-1000:1,200-1000:1, amino acid-base solution and raw material fullerene/raw material are embedded into gold
Belong to fullerene to be mixed；(c) by 40-80 DEG C of reaction of said mixture, (optional, the reaction is small to be stirred to react 1-7
When), it is filtered to remove unreacted a small amount of solid powder；(d) filtrate dialysis removes small molecular weight impurity, and after filtering, what is obtained is dark brown
Color solution is water-soluble fullerene/embedded metal fullerene of the amino acid modification of the present invention.Optionally, dialysis is used
Bag filter molecular cut off Mw=3500；Optionally, the aperture 200- of miillpore filter used in the filtering after dialysis
220nm；Optionally, the conductivity dialysed to liquid outside bag filter is less than 1 μ s/cm.
Above application, method or pharmaceutical composition in another embodiment, the water-soluble amino acids for alanine,
At least one of glycine, serine, arginine, lysine and tianmenine.
Above application, method or pharmaceutical composition in another embodiment, described in water-soluble modified method (1)
Aqueous slkali is sodium hydroxide solution or potassium hydroxide solution.
Above application, method or pharmaceutical composition in another embodiment, solid-liquid in water-soluble modified method (1)
Reaction includes weighing 50~200mg C60Solid or C70Solid or Gd@C82The dioxygen of solid and 3~15ml 20~40%
Water, the aqueous slkali of 2~10ml 5~20%, hybrid reaction is all dissolved to solid under conditions of 50~100 DEG C, then uses second
Alcohol washs, and dialysis obtains corresponding hydroxylation derivative, i.e. water-soluble fullerene structure.Optionally, it dialyses to bag filter external solution
The conductivity of body is less than 1 μ s/cm.In the description herein, performance is proportionate relationship between each substance, in practical application not by
The limitation of 50~200mg, 5~15ml and the specific reaction scales of 2~10ml, can proportionally be enlarged.
Above application, method or pharmaceutical composition in another embodiment, the raw material fullerene include it is a kind of or
A variety of general formulas are C2mThe cage structure being made of carbon atom, 30≤m≤60, such as；C60, C70, C84Deng.
Above application, method or pharmaceutical composition in another embodiment, the raw material embedded metal fullerene packet
Include M@C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2nAnd MxA3-xN@C2nIn it is one or more,
In：M, A represents metallic element and M, A are selected from any one in lanthanide element, Sc and Y, 30≤n≤60,0≤x
≤3.N represents nitrogen, and C represents carbon, and S represents element sulphur, lanthanide element include La, Ce, Pr, Nd, Pm, Sm, Eu,
Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
Above application, method or pharmaceutical composition in another embodiment, the fatty liver for obesity fatty liver,
Hyperlipemia-fatty liver, diabetes fatty liver, alcoholic fatty liver or Drug fatty liver.
In another embodiment, the treatment fatty liver includes for above application, method or pharmaceutical composition：1) make liver
The content of dirty middle free fatty tends to be normal；2) it (can be the reduction of vacuole quantity or volume to reduce diffusivity fat vacuole
Reduce)；3) improve liver function, making liver function index, (liver function index includes：Glutamic-pyruvic transaminase, glutamic-oxalacetic transaminease) tend to just
Often；4) liver weight is reduced；5) redox improved in liver is horizontal, makes SOD active, and CAT activity and MDA contents are restored just
Often；6) (blood lipids index includes reduction blood fat：T-CHOL, triglycerides, high/low density fat).
Drug or aforementioned pharmaceutical compositions in above application in another embodiment, the drug or pharmaceutical composition
Can be that tablet, pill, powder, pastille, sachet, cachet, elixir, suspending agent, emulsion, solution, syrup, gas are molten
Glue, ointment, soft hard gelatin capsule, suppository, aseptic injectable solution or aseptic packaging powder-injection preparation.It will be effective in the present invention
Ingredient is prepared into drug or method known to a person of ordinary skill in the art can be used to prepare in the method for pharmaceutical composition, makes it
Quick-release, sustained release or sustained release active ingredient after subject is applied to, such as：Active ingredient can be mixed with carrier, with load
Body is diluted or is encapsulated in the carrier.
Drug or aforementioned pharmaceutical compositions in above application in another embodiment, suitable for as carrier, figuration
Some of agent and diluent examples include lactose, dextrose, sucrose, sorbierite, mannitol, starch, resin, Arabic gum, phosphorus
Sour calcium, alginate, tragacanth, gelatin, calcium silicates, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, aqueous syrup
(water syrup), methylcellulose, methyl hydroxybenzoate and propyl ester, talcum powder, magnesium stearate and liquid paraffin.
Drug or aforementioned pharmaceutical compositions in above application in another embodiment, the drug or pharmaceutical composition
The auxiliary agents such as lubricant, wetting agent, emulsification and suspending agent, preservative, sweetener or corrigent can also be also comprised.
Drug or aforementioned pharmaceutical compositions in above application in another embodiment, when the drug or the medicine
Compositions in liquid form in the presence of, a concentration of 0.01- of the active ingredient in the drug or described pharmaceutical composition
50mg/mL is optionally 0.01-10mg/mL, 0.01-20mg/mL, 0.01-30mg/mL, 0.01-40mg/mL；When the medicine
Object or described pharmaceutical composition in solid form in the presence of, concentration of the active ingredient in the drug or described pharmaceutical composition
It is optionally 0.01-10mg/g for 0.01-50mg/g, 0.01-20mg/g, 0.01-30mg/g, 0.01-40mg/g.
In another embodiment, the subject is human or animal to the above method, and animal can be mammal, such as
Mouse, cavy, rat, dog, rabbit, monkey etc..
In another embodiment, the administration dosage of the active ingredient is 1mg/kg/d-500mg/kg/ to the above method
D is optionally 1-100mg/kg/d, 1-20mg/kg/d, 1-10mg/kg/d, can be -30 days 5 days using the course for the treatment of, according to disease
Feelings can be taken or take for a long time in short term；The method of application of active ingredient can be oral, intravenous injection or intraperitoneal administration.
Term used herein " treatment " includes its generally accepted meaning, which includes preventing, prevention, press down
The development of symptom produced by making, improve and slow down, stop or reversing or expected lesion.As such, the present invention cover it is therapeutic and
Preventative application.
Term used herein " active ingredient ", " active ingredient water-soluble fullerene structure " or " water-soluble fullerene
Structure " refers to water-soluble fullerene, water-soluble embedded metal fullerene, water-soluble fullerene and water-soluble interior
At least one of pharmaceutical salt of the composition of engaged column fullerene, the pharmaceutical ester of above three and more than three.
Term used herein " effective quantity " refer to active ingredient through it is single or multiple be applied to patient and to diagnosing or
The patient treated provides the amount or dosage of intended effect.Effective quantity can be by the diagnostician that is participated in as people in the art
The observation result of member's gained by known technology and under similar situation is and determining.It is determining to apply the effective of active ingredient
When amount or dosage, the diagnostician participated in is considered as many factors, and the factor includes but not limited to：The kind of mammal
Belong to；Volume, age and general health；Involved disease specific；The disease involves in degree or severity；Individual patient
Response；The particular compound applied；Mode of administration；The bioavailability characteristics of applied preparation；Selected dosage regimen；
The use of concomitant drugs therapy；And other relevant situations.
Term used herein " raw material fullerene ", be not added with any qualifier " fullerene " each mean not pass through water
Soluble modified fullerene, i.e. fullerene ontology.
Term used herein " raw material embedded metal fullerene ", " the embedded metal fullerene " for being not added with any qualifier
It each means not by water-soluble modified embedded metal fullerene, i.e. embedded metal fullerene ontology.
Term used herein " water-soluble fullerene " refers to what fullerene ontology obtained after water-soluble modified
Water-soluble modified fullerene.
Term used herein " water-soluble embedded metal fullerene " refers to that embedded metal fullerene ontology passes through water
The water-soluble modified embedded metal fullerene obtained after soluble modified.
In order to facilitate metering, all about water-soluble fullerene in the present invention, water-soluble metal fullerene concrete content,
The quantitative restriction such as concentration is with concrete content, concentration of its corresponding fullerene ontology or embedded metal fullerene ontology etc.
Come what is weighed, such as：The administration dosage of active ingredient refers to that the every 1 day mouse per 1kg will apply for 1mg/kg/d-500mg/kg/d
The amount of corresponding fullerene ontology carbon cage is 1mg-500mg in active ingredient.
Compared with prior art, beneficial effects of the present invention are：
1st, raw material fullerene and raw material embedded metal fullerene is made to realize water solubility in the present invention, is to make it in biology
It in vivo as blood circulation is delivered to liver, plays a role in liver, so as to improve the lipid-metabolism of liver, reduces free-fat
Acid reduces fat bubble in liver, reduces the content of triglycerides, hence it is evident that improving liver function makes glutamic-pyruvic transaminase and glutamic-oxalacetic transaminease
Content tends to be normal, achievees the effect that efficiently to treat fatty liver.Meanwhile the efficient treatment of fatty liver is also fundamentally avoided
Fatty liver develops into the possibility of the severes such as steatohepatitis, liver fibrosis, hepatic sclerosis, latter stage hepatic failure or liver cancer.
2nd, after active ingredient water-soluble fullerene structure enters liver in the present invention, because it is with good removing free radical
Effect, can to liver carry out " cleaning ", improve liver in redox level.
3rd, the entrance of active ingredient water-soluble fullerene structure in vivo can be with tachymetabolism in the present invention, will not to intracorporeal organ
It is toxic.
Description of the drawings
Attached drawing 1 is the C that embodiment 1 is prepared70The thermogravimetric analysis of corresponding hydroxylation derivative and differential thermogravimetric curve.
Attached drawing 2 is Gd@C82(OH)nElectron spin nuclear magnetic resonance (ESR) figure of material.
Attached drawing 3 is 1 gained Gd@C of embodiment82(OH) distribution of metabolism for 24 hours of n materials in vivo.
The mouse liver H＆E staining versus figure that attached drawing 4 is each group in the embodiment of the present invention 5.
Attached drawing 5 is the content of the triglycerides in Mice Body after being administered 2 weeks in the embodiment of the present invention 5.
The content that attached drawing 6 is glutamic-pyruvic transaminase ALT in Mice Body after being administered 2 weeks in the embodiment of the present invention 5.
The content that attached drawing 7 is glutamic-oxalacetic transaminease AST in Mice Body after being administered 2 weeks in the embodiment of the present invention 5.
Attached drawing 8 is 6Gd@of embodiment of the present invention C82(OH)13(NHCH2CH2COOH)6Thermogravimetric analysis and differential thermogravimetric curve.
Attached drawing 9 is 6Gd@of embodiment of the present invention C82(OH)13(NHCH2CH2COOH)6Infrared spectrogram.
Attached drawing 10 is mouse liver percentage of liveweight ratio chart after being treated in the embodiment of the present invention 8, and N.S. represents physiological saline, GF
Represent Gd@C82(OH)13(NHCH2CH2COOH)6, i.e., from left to right each group is respectively：Blank+physiological saline group, blank+GF groups,
Model group, treatment group -0.375mM, treatment group -0.75mM and treatment group -1.5mM.
Attached drawing 11 is mouse liver HE coloring pathological section figures after being treated in the embodiment of the present invention 8.
Attached drawing 12 is mouse liver oil red stained slice figure after being treated in the embodiment of the present invention 8.
Attached drawing 13 is mouse liver lipid relative amount figure after being treated in the embodiment of the present invention 8.
Attached drawing 14 is that mice serum ALT and AST contain spirogram after being treated in the embodiment of the present invention 8.
Attached drawing 15 is each group mouse liver percentage of liveweight ratio bar graphs in the embodiment of the present invention 9, and # represents the P compared with A groups<
0.05, * represents the P compared with C groups<0.05.
Attached drawing 16 is each group mouse liver inner lipid content histogram in the embodiment of the present invention 9, and ## represents the P compared with A groups<
0.01, * represents the P compared with C groups<0.05.
Attached drawing 17 is each group mouse liver HE coloring pathological sections in the embodiment of the present invention 9.
Attached drawing 18 is mouse serum alt and AST content histograms in the embodiment of the present invention 9.
Specific embodiment
Below in conjunction with the accompanying drawings, the specific embodiment of the present invention is described in detail, it is to be understood that the guarantor of the present invention
Shield range is not restricted by specific implementation.The raw materials used Gd@C of following embodiment82Solid powder is bought in Xiamen Fu Na
New material Science and Technology Ltd., molecular weight 1141, purity 99.1%.The raw materials used C of following embodiment60Solid powder purchase in
Xiamen good fortune is taken in the fresh material Science and Technology Ltd., molecular weight 720, purity 99%.The raw materials used C of following embodiment70Solid powder is purchased
It buys and takes in the fresh material Science and Technology Ltd. in Xiamen good fortune, molecular weight 840, purity 99%.
The preparation of embodiment 1, water soluble hydroxy fullerene structure
Weigh 100mg C60Solid or 100mg C70Solid or 100mg Gd@C82Solid, the hydrogen peroxide of 7ml 30%, 3ml
10% sodium hydroxide solution reacts under conditions of 50 DEG C, until powder all dissolves, is then washed with ethyl alcohol, dialyses, obtains
Corresponding hydroxylation derivative, i.e. water-soluble fullerene structure.
10% sodium hydroxide solutions of 3ml therein are substituted for a certain amount of 30% ammonium hydroxide, other steps are according to above-mentioned side
Progress in method obtains corresponding amination derivative, i.e. water-soluble fullerene structure.
Contain more liquid in the hydroxylation derivative of gained or amination derivative after dialysis, can also be concentrated
Obtain solid, but regardless of whether concentrated, raw material fullerene/raw material embedded metal fullerene it is water-soluble modified complete
Into, if concentrated do not influence it is water-soluble modified after fullerene/embedded metal fullerene use, as long as adjusted to
Suitable concentration.
Embodiment 2,
The C that above-described embodiment 1 is prepared70Corresponding hydroxylation derivative (hereinafter referred to as C70- OH) divide into row element
It analyses (Flash EA 1112), and combines thermogravimetric and the interpretation of result of difference quotient thermogravimetric it connects hydroxyl value.In the result of elemental analysis
In, the C70In-OH, C content 37.85%, H content 1.51%, N content<0.3%.From 1 thermogravimetric analysis of attached drawing it is found that
C70Contain 3.7% water in-OH solid powders, about 5 hydrones, can with reference to the ratio of H content in elemental analysis and C content
Calculate 24 hydroxyls of carbon cage surface modification.So C70The average formula of-OH is C70(OH)24·5H2O。
The Gd@C that above-described embodiment 1 is prepared82Corresponding hydroxylation derivative (hereinafter referred to as Gd@C82(OH)n) into
Row element is analyzed, C content 76.6%, H content 0.89%, and N content is less than 0.6%.
Embodiment 3, water solubility embedded metal fullerene Gd@C82(OH)nScavenging ability detects
The present invention detects water-soluble embedded metal fullerene Gd@C by Electron Spin Resonance Spectra (ESR)82(OH)nClearly
Except the ability of free radical.
Detection method：The method that hydroxyl radical free radical is generated using uv induction, by the dioxygen that 50 μ L mass concentrations are 39%
The dimethyl pyridine N-oxide of water, 50 μ LPBS buffer solutions (pH=7.4) and micro (0.133mM) (catch by DMPO, free radical
Obtain agent) solution mixing, control group direct irradiation is ultraviolet, and experimental group adds in being prepared according to method in embodiment 1 for 20 μ L immediately
10 μ L of water-soluble embedded metal fullerene water solution, and respectively use 280nm ultraviolet light 4min, detection free radical letter
Number.As shown in Figure 2, non-sweep is without adding in the water-soluble embedded metal fullerene Gd obtained by according to 1 method of embodiment
C82(OH) blank control of n, sweep is adds in Gd@C82(OH) experimental group sample of n compared with blank control, adds in Gd@
C82(OH)nThe signal of sample is substantially reduced, and illustrates to add in Gd@C82(OH)nFree radical existing for the experimental group of sample is less, Gd@
C82(OH)nThere is strong Scavenging ability.
Embodiment 4, water solubility embedded metal fullerene Gd@C82(OH)nInternal metabolism
Take the Gd@C prepared according to the method in embodiment 1 of a concentration of 1mM82(OH)n200 μ L by be injected intraperitoneally into
Enter in C57 Mice Bodies, normal raising is dissected afterwards for 24 hours, takes mouse organs' heart, liver, spleen, lung, kidney, and pancreas is weighed, and with 65%
Nitric acid resolution overnight, gadolinium ion concentration is measured after 50 times of dilution under conditions of 120 DEG C by ICP.In attached drawing 3, it can see
Go out water-soluble embedded metal fullerene Gd C82(OH)nIt is enriched in pancreas far more than the heart, kidney, lung and spleen.
Embodiment 5, water solubility embedded metal fullerene Gd@C82(OH)nTreatment to fatty liver
(1) experimental method
The Models of Fatty Liver mouse of experiment is db/db mouse, this mouse is that leptin receptor gene defect leads to obesity, so
The model of more serious fatty liver is developed into afterwards.Purchased from Nanjing zootype center, quoted from Jackson Lab of the U.S..
Experimental animal is divided into 3 groups, every group 6.A groups take the mouse of 6 fat-free livers of db/m, and as blank group, administration is controlled
Treat the physiological saline for application and drug same volume used in C groups；B groups take 6 db/db mouse as model group, drug treatment
For application and the physiological saline of drug same volume used in C groups；C groups take 6 db/db mouse as Gd@C82(OH)nExperimental group,
Drug treatment is the Gd@C prepared using the method according to embodiment 182(OH)n.A-C groups are by the way of intraperitoneal administration, respectively
The week old of group mouse started to be administered into the 10th week, was administered once daily, dosage 10mg/kg/d, successive administration two weeks.
(2) experimental result
The present invention by administration after put to death mouse, H＆E pathological sections are carried out, and take its serum to the liver organ of mouse
Carry out liver function index glutamic-pyruvic transaminase ALT, the detection of glutamic-oxalacetic transaminease AST and the detection of blood fat triglycerides, detection
As a result it is as follows.
1) H＆E is tested
Mouse is put to death after being administered 2 weeks, the liver of mouse is taken to be fixed in 4% formaldehyde, then paraffin embedding, is sliced, dye
Color.As shown in Figure 4, blank group is normal mouse, and liver structure is normal, fat-free bubble, and model group is with fat
Liver but the mouse for only receiving saline therapy have a large amount of white vacuole, i.e. fat in the liver of it can be seen from the figure that mouse
Fat steeps, and passes through the Gd@C prepared according to the method for embodiment 182(OH)nFat bubble in the liver of the experimental mice for the treatment of
It significantly reduces, it was demonstrated that water-soluble fullerene/metal fullerene composition has good effect to treatment fatty liver.
2) content of triglycerides
After mouse is administered 2 weeks, eye socket takes blood, after whole blood, blood sample is taken to be stored at room temperature 1h, 3500rpm centrifugation 15min,
Upper serum is drawn, the content of triglycerides TG is measured by automatic blood biochemistry instrument, as shown in Figure 5, model group is compared to sky
The amount of white group triglycerides TG is significantly raised, this is because the extremely caused content of triglyceride of fat metabolism caused by fatty liver
Increase, and treatment group the results show that through according to embodiment 1 method preparation Gd@C82(OH)nThe glycerine of mouse after treatment
Three ester contents are substantially reduced, it was demonstrated that it has treatment fatty liver, reduces the effect of blood fat.
3) liver function index is tested
After mouse is administered 2 weeks, eye socket takes blood, takes whole blood, and after being stored at room temperature 1h, 3500rpm, 15min draw upper strata blood
Clearly, the content of liver function index glutamic-pyruvic transaminase ALT and glutamic-oxalacetic transaminease AST is measured by automatic blood biochemistry instrument.Such as 6 He of attached drawing
Shown in 7, compared to blank group, the glutamic-pyruvic transaminase ALT contents of model group are significantly raised, and pass through the method according to embodiment 1
The Gd@C of preparation82(OH)nThe glutamic-pyruvic transaminase ALT contents of the experimental mice for the treatment of are substantially reduced, and tend to be normal.Millet straw turns ammonia
Enzyme AST also has corresponding rule, it was demonstrated that by Gd@C82(OH)nThe liver function of mouse is obviously improved after treatment.
Above-described embodiment treats the db/db mouse for suffering from fatty liver, the results showed that water-soluble fullerene knot
Structure can effectively reduce fat bubble, reduces blood fat and improve liver function.
The preparation of embedded metal fullerene structure that embodiment 6, water-soluble amino acids are modified
10mg Gd@C82Solid is added in single port bottle, adds in Beta-alanine-hydroxide that NaOH mass fractions are 14%
(dissolved with alanine and sodium hydroxide in ie in solution, wherein 14%) mass fraction of sodium hydroxide is, makes Beta-alanine to sodium solution
Molar ratio with sodium hydroxide is specially 1：2；Make Beta-alanine and Gd@C82Molar ratio be 1000：It is vigorously stirred at 1,50 DEG C
1.5h, black solid gradually dissolve generation dark brown solution.Unreacted a small amount of solid powder is filtered to remove, filtrate uses ethyl alcohol
Washing, the dialysis of Mw=3500 bag filters remove small molecular weight impurity, use the dark brown solution obtained after 220nm filtering with microporous membrane
The embedded metal fullerene structure of water-soluble amino acids modification as of the invention.
Embodiment 7
Gd@C are used to embodiment 682The embedded metal fullerene structure of water-soluble amino acids modification being prepared carries out
Elemental analysis and thermogravimetric curve analysis, the results are shown in table below for elemental analysis, and thermogravimetric curve analysis is as shown in Figure 8：
The elemental analysis result of the embedded metal fullerene structure of Beta-alanine modification
It can be obtained in the embedded metal fullerene structure of water-soluble amino acids modification and contained according to thermogravimetric curve analysis
10.9% water is about 13 H by calculating2O molecules in conjunction with elemental analysis, further speculate and obtain being averaged for the substance
Molecular formula is Gd@C82(OH)13(NHCH2CH2COOH)6, hereinafter referred to as GF.
Fig. 9 is infrared spectrum in 3300cm-1The strong absorption peak of left and right is attributed to the stretching vibration of O-H, in 1740 Hes
1630cm-1Locate medium absorption peak and be attributed to the stretching vibration of C=O, the bending vibration of N-H, in 1568,1400 and 1300cm-1
The strong peak at place is respectively the stretching vibration peak of the stretching vibration of C=C, the bending vibration of O-H and C-O, C-N.As shown in Figure 9,
Containing above-mentioned hydrophilic radical in the embedded metal fullerene structure of Beta-alanine modification of the present invention, i.e., it is water-soluble.
Treatment of the embedded metal fullerene structure that embodiment 8, water-soluble amino acids are modified to fatty liver
The notable feature of non-alcoholic fatty liver disease (NAFLD) shows as hepatic steatosis, the i.e. lipids such as triglycerides
It is deposited in the cytoplasm of liver cell in the form of fat drips, therefore liver can become loose, quality increases, liver percentage of liveweight ratio
Raising.
(1) Experiment on therapy
This experiment employs ob/ob mouse, and ob/ob mouse are a kind of leptin secretion gene defection type obesity mouse,
Leptin (a kind of protein hormone can participate in the metabolism of internal carbohydrate and fat) cannot be normally generated in vivo, therefore is lacked
The ob/ob mouse meeting excess ingestion food of leptin secretion, relative to the normal mouse of the non-defect of leptin secretion gene, ob/ob is small
Mouse weight significantly increases, and build becomes larger, and develops into more serious Models of Fatty Liver.The mouse is purchased from Nanjing University-Nanjing biology
Medicine Research Academy, quoted from Jackson Lab of the U.S..
This experiment mice is divided into 6 groups, i.e.,：Blank+physiological saline group, blank+GF groups, model group, treatment group -0.375mM,
Treatment group -0.75mM, treatment group -1.5mM, every group of 6 mouse.Blank+physiological saline group, blank+GF groups are not suffer from fat
The background mice of fat liver starts to be administered on the 6th week after blank+physiological saline group, blank+GF group mouse births, it is average during administration
Weight is 23g；Model group, treatment group -0.375mM, treatment group -0.75mM, treatment group -1.5mM are ob/ob mouse, mouse
Start to be administered within the 6th week after birth, its average weight is 33g during administration.The mode being administered in above-mentioned each group is according to the following contents
It carries out.
Blank+physiological saline group：Administration is 150 μ l physiological saline of intraperitoneal injection to mouse every time.It is administered once a day, continues
16 days.
Blank+GF groups：Administration is that water-soluble metal fullerene GF prepared by intraperitoneal injection embodiment 6 is prepared to mouse every time
150 μ l of 1.5mM solution.It is administered once a day, continues 16 days.
Model group：Administration is 150 μ l physiological saline of intraperitoneal injection to mouse every time.It is administered once a day, continues 16 days.
Treatment group -0.375mM：The mouse water-soluble metal fullerene GF that administration is prepared for intraperitoneal injection embodiment 6 every time
The 150 μ l of 0.375mM solution of preparation.It is administered once a day, continues 16 days.
Treatment group -0.75mM：Mouse every time for water-soluble metal fullerene GF prepared by intraperitoneal injection embodiment 6 match by administration
The 150 μ l of 0.75mM solution of system.It is administered once a day, continues 16 days.
Treatment group -1.5mM：Mouse every time for water-soluble metal fullerene GF prepared by intraperitoneal injection embodiment 6 match by administration
The 150 μ l of 1.5mM solution of system.It is administered once a day, continues 16 days.
(2) pathology and physical signs of hepatic steatosis
(# and ## represent to represent have significantly with model group with the significant difference of blank control group, * and * * as shown in Figure 10
Sex differernce), the liver index (liver percentage of liveweight percentage) of model group ob/ob mouse is significantly higher than the health back of the body for not suffering from fatty liver
Scape mouse, but after being treated using water-soluble metal fullerene, the Liang Ge treatment groups (0.75mM and 1.5mM) of higher concentration
Liver index is decreased obviously, and close to normal level, has been confirmed GF and has been played therapeutic effect to nonalcoholic fatty liver.
Pathological section then more intuitively illustrates that GF materials can improve the hepatic steatosis of ob/ob mouse, Tu11Fen
It is not result of each group murine liver tissue HE coloring pathological sections under different amplification.Therefrom it can be found that model group ob/
There is the swelling of liver cell of large area in the liver of ob mouse, and cytoplasm is loose, and lipid accumulation is in figure at white vacuole, nucleus
Cell edges are extruded to, basic lobuli hepatis structure is destroyed, and only remaining cytoskeleton is visible；Low concentration treatment group
The improvement of (0.375mM) is in confused situation aobvious, only can be found that a seldom part improves in the liver cell of portal area, liver group
The rest part knitted still is occupied by the fat vacuole of large area；Middle concentration treatment group (0.75mM) then has obvious improvement,
Although being can be found that from HE stained slices and more lipid vacuole being still distributed in hepatic tissue, the structure of lobuli hepatis obtains
Restore, compared with the ob/ob mouse without treatment, middle concentration treatment group structural integrity has tangible liver cell and increases
Add, nucleus is largely also at normal position；The liver structure recovery of high concentration treatment group (1.5mM) is more controlled better than other
Treatment group, the liver cell of lobuli hepatis portal area restore normal completely, and marshalling forms orderly liver plate and hepatic sinusoid structure, only
There is liver cell of each lobuli hepatis far from portal area still to will appear some lipid vacuoles, with the ob/ob mouse without treatment
Liver is compared, and the situation of hepatic steatosis has been obtained for largely improving.In addition, the health with not suffering from fatty liver
The control group of mouse peritoneal injecting normal saline is compared, and healthy mice is injected intraperitoneally the normal saline solution of sample GF in pathology
It is upper that there is no generate harmful effect to liver.
Lipid specific stain can be Chinese red, therefore the dyeing of liver oil red can intuitively reflect liver by oil red dyeing
Situation existing for dirty inner lipid, Figure 12 are that each group mouse liver oil red dyes the result under different amplification respectively.Normally
Mouse liver cell in be not in fat drips, therefore bluish violet is still presented after oil red dyeing, and the oil red of ob/ob mouse livers contaminates
Color slice on it can be seen that large area Chinese red fat drips, after being treated using GF materials, fat drips preferentially from comprising portal vein,
It is reduced around the portal area of arteria hepatica and bile duct, it is consistent with the result that HE stained slices are shown.Oil red coloration result is carried out
Photodensitometry can more intuitively compare the lipid content in liver between each group, as shown in figure 13 (# and ## is represented and blank
The significant difference of control group, * and * * are represented and the significant difference of model group), be not in be contaminated in normal mouse liver
Into the fat drips of Chinese red, and ob/ob mouse use the GF normal saline solutions intraperitoneal injection 16 of 0.375mM, 0.75mM and 1.5mM
After it, compared with the ob/ob mouse (i.e. model group) of intraperitoneal injection of saline, liver inner lipid content has dropped respectively
40%th, 60% and 85%, this proves that GF materials can be very good to improve the symptom of fatty liver by intraperitoneal injection, reduces in liver
Lipid content.
In addition, the glutamic-pyruvic transaminase (GPT) (ALT) and aspartat aminotransferase (AST) content in serum are also
Reflect an important indicator of liver function.Because ALT and AST are primarily present in liver cell endochylema, only liver cell by
It can be just discharged into blood in the case of damage, and can have a very long time in blood, so both in serum
The content of enzyme can embody the degree of liver damage.(# and ## are represented and the significant difference of blank control group as shown in figure 14
Different, * and * * are represented and the significant difference of model control group), the left side and the right represent serum alt respectively in each group of column
With the content of AST, it is seen that the model group ob/ob mouse with fatty liver substantially increase since liver cell is damaged serum alt and AST
Add, Serum ALT and AST contents decline after being treated using water-soluble metal fullerene GF, and treatment group is respectively provided with compared with model group
Significant difference illustrates that the situation that is damaged of liver cell has obtained alleviating and gradually restored normal.
Embodiment 9C70Treatments of-the OH to fatty liver
1st, experimental animal
C57BL6/J mouse of this experiment modeling mouse used for 5 week old, male, average weight 23.31g.
10 weeks structure model fatty liver mouse of 30% fructose water and fed standard chow, 30% fruit are used when C57BL6/J mouse are 5 weeks big
The average weight of the mouse of syrup and fed standard chow after 10 weeks be 30.26g, it is confirmed its all with fatty liver；Remaining 5
The C57BL6/J normal mouses of week old use aqua sterilisa and fed standard chow to be fed as control, aqua sterilisa and standard feed for 10 weeks
The average weight of normal control mice after supporting 10 weeks is 27.70g.
2nd, experiment packet
Experimental animal is divided into 4 groups, every group 6, and each group is respectively：
A groups are normal mouse+physiological saline group：Normal mouse of this group of mouse not suffer from fatty liver, Therapy lasted 3
Week, on every Mondays, three, five tail vein injection salines, injection volume 5ml/kg；
B groups are normal mouse+C70- OH normal saline solution groups：Normal mouse of this group of mouse not suffer from fatty liver, it is real
Test it is for 3 weeks, on every Mondays, three, five tail vein injection C70The C of a concentration of 2.5mg/ml of-OH70- OH normal saline solutions, injection
Measure 5ml/kg, C70- OH is that C is prepared in embodiment 170Corresponding hydroxylation derivative；
C groups are model mice+physiological saline group：Model mice suffers from fatty liver, Therapy lasted 3 weeks, on every Mondays, three, five
Tail vein injection saline, injection volume 5ml/kg；
D groups are model mice+C70- OH normal saline solutions (2.5mg/ml) group：Model mice suffers from fatty liver, and experiment is held
Continuous 3 weeks, on every Mondays, three, five tail vein injection C70The C of a concentration of 2.5mg/ml of-OH70- OH normal saline solutions, injection volume
5ml/kg, C70- OH is that C is prepared in embodiment 170Corresponding hydroxylation derivative.
Above-mentioned Therapy lasted 3 weeks, during which statistical weight, blood of finally drawing materials, each organ and tissue are fixed or are frozen respectively
It remains further to test after depositing.
3rd, experimental result
(1) liver index
Lipid accumulation is so that liver mass increases in liver, and percentage of liveweight ratio increases, therefore (liver mass accounts for liver index
Percent weight) it can reflect the situation of fat accumulation in liver.As shown in Figure 15, the C groups of 30% fructose soln of feeding
Mouse liver percentage of liveweight ratio is dramatically increased relative to A groups, D group tail vein injections C70After-OH normal saline solutions under liver index
Drop, and D groups significant difference compared with C groups, illustrate C70- OH has fatty liver using tail vein injection certain treatment effect
Fruit.
(2) pathological section
HE dyeing is carried out to the hepatic tissue of each group mouse respectively and oil red dyes, and optical density analysis is dyed oil red and tied
Fruit carries out semi-quantitative analysis.As shown in Figure 16, lipid content increases in C groups, with the lipid content in A group normal mouse livers
Compared to good significant difference, and the liver lipids content of D groups treatment mouse is remarkably decreased, liver in mouse after treatment
Dirty accumulation is reduced.
Attached drawing 17 is the result of each group mouse liver HE coloring pathological sections.The mouse liver of 30% fructose water of feeding is universal
There is hydropic degeneration, the increase of liver cell volume, the loose light dye of cytoplasm, portal area damage is serious compared with other sections, goes out in liver cell
Existing sheet vacuole.Tail vein injection C70Mouse liver lesion degree is improved after-OH.
(3) serum blood biochemistry index
Attached drawing 18 is ALT and AST content statistical charts in each group mice serum, and it is thin that serum alt and AST contents reflect liver
Born of the same parents are damaged degree of necrosis, it is seen that the mice serum ALT and AST fed using 30% fructose water only has slight rising, does not show
Sex differernce is write, the ALT/AST levels decline of D group mouse is corresponding with the conclusions such as liver index, pathology.
To sum up, the C of tail vein injection 2.5mg/ml concentration70The fatty liver that-OH normal saline solutions induce fructose is controlled
Treatment acts on.
The description of the aforementioned specific exemplary embodiment to the present invention is in order to illustrate and illustration purpose.These descriptions
It is not wishing to limit the invention to disclosed precise forms, and it will be apparent that according to the above instruction, can much be changed
And variation.The purpose of selecting and describing the exemplary embodiment is that explain that the specific principle of the present invention and its reality should
With so that those skilled in the art can realize and utilize the present invention a variety of different exemplary implementations and
Various chooses and changes.The scope of the present invention is intended to be limited by claims and its equivalents.
Claims (10)
1. a kind of water-soluble fullerene, water-soluble embedded metal fullerene, the water-soluble fullerene and described water-soluble
The pharmaceutical salt of the composition of the embedded metal fullerene of property, the pharmaceutical ester of above three or more three are controlled in preparation
Treat the application in the drug of fatty liver.
2. a kind of pharmaceutical composition for treating fatty liver, it is characterised in that：Including at least one active ingredient selected from the group below：Water
The fullerene of dissolubility, water-soluble embedded metal fullerene, the water-soluble fullerene and the water-soluble embedded metal
The composition of fullerene, the pharmaceutical ester of above three, above three pharmaceutical salt, described pharmaceutical composition further includes
At least one of pharmaceutical carrier, pharmaceutical diluent and pharmaceutical excipient.
3. the pharmaceutical composition described in application according to claim 1 or claim 2, it is characterised in that：It is described water-soluble
The fullerene of property be selected from the group in it is one or more：(1) carbon cage outer surface is modified with the fullerene of hydrophilic radical；(2) carbon cage
The fullerene that outer surface is wrapped up by hydrophily biological micromolecule；(3) fowler loaded by the carrier material with biocompatibility
Alkene；(4) the water-soluble supramolecular system fullerene being self-assembly of；During the water-soluble embedded metal fullerene is selected from the group
It is one or more：(1) carbon cage outer surface is modified with the embedded metal fullerene of hydrophilic radical；(2) carbon cage outer surface is hydrophilic
Property biological micromolecule package embedded metal fullerene；(3) embedded metal loaded by the carrier material with biocompatibility
Fullerene；(4) the water-soluble supramolecular system embedded metal fullerene being self-assembly of.
4. the pharmaceutical composition described in application according to claim 3 or claim 3, it is characterised in that：It is described hydrophilic
Group includes one or more in hydroxyl, carboxyl, sulfydryl, amino and water-soluble amino acids residue；Optionally, the water solubility
Amino acid residue is alanine residue, glycine residue, serine residue, arginine residues, lysine residue and tianmenine
At least one of residue.
5. the pharmaceutical composition described in application according to claim 3 or claim 3, it is characterised in that：
The general formula of the water-soluble fullerene is C2a(OH)b(Amino Acid)c, Amino Acid represent water-soluble amino acids
Residue；30≤a≤60, optional a are 30 or 35；0<b<50, optional 0<b<30, also optional b=13,20,22,24 etc.；0
≤c<20, optional c=2-15, also optional c=6；
The general formula of the water-soluble embedded metal fullerene is M@C2d(OH)e(Amino Acid)f, Amino Acid represent water
Dissolubility amino acid residue；M is selected from rare earth metal, and optional rare earth metal is Gd, La etc.；30≤d≤60, optional d for 41 or
30 or 35；0<e<50, optional 0<e<30, also optional e=13,20,22,24 etc.；0≤f<20, optional f=2-15, also
Optional f=6.
6. the pharmaceutical composition described in application according to claim 1 or claim 2, it is characterised in that：It is described water-soluble
Property fullerene be by carrying out water-soluble modified acquisition to raw material fullerene；The water-soluble embedded metal fullerene is
By carrying out water-soluble modified acquisition to raw material embedded metal fullerene.
7. the pharmaceutical composition described in application according to claim 6 or claim 6, it is characterised in that：
It is C that the raw material fullerene, which includes one or more general formulas,2mThe cage structure being made of carbon atom, 30≤m≤60；
The raw material embedded metal fullerene includes M@C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2nWith
MxA3-xN@C2nIn it is one or more, wherein：M, A represents metallic element and M, A are selected from lanthanide element, Sc and Y
Any one, 30≤n≤60；0≤x≤3；N represents nitrogen, and C represents carbon, and S represents element sulphur, lanthanide element
Including La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
8. the pharmaceutical composition described in application according to claim 6 or claim 6, it is characterised in that：It is described water-soluble
Property be modified selected from following methods one kind：
(1) preparation method that surface modification has water-soluble fullerene/embedded metal fullerene of hydroxyl includes：By raw material fowler
At least one of alkene and raw material embedded metal fullerene are mixed and are reacted with hydrogen peroxide and aqueous slkali, then washs dialysis；
(2) surface modification has the preparation method packet of water-soluble fullerene/embedded metal fullerene of hydroxyl and amino acid residue
It includes：(a) using water-soluble amino acids and NaOH/KOH prepare water soluble amino acid-base solution (it is optional, water-soluble amino acids and
The molar ratio of NaOH/KOH is 1:1-10, also optional is 1:2 or 1:1-8；Optionally, in water soluble amino acid-base solution
The mass fraction of NaOH/KOH can be 10~50%, and also optional is 14% or 10~30%)；(b) according to amino acid and raw material
Fullerene/raw material embedded metal fullerene molar ratio is 1-1000:1, it is optionally 50-1000：1,100-1000:1,200-
1000:1, amino acid-base solution is mixed with raw material fullerene/raw material embedded metal fullerene；(c) by said mixture
40-80 DEG C of reaction (optional, the reaction is is stirred to react 1-7 hours), is filtered to remove unreacted a small amount of solid powder；
(d) filtrate dialysis removes small molecular weight impurity, filtering.
9. the pharmaceutical composition described in application according to claim 1 or claim 2, it is characterised in that：The fat
Liver is obesity fatty liver, hyperlipemia-fatty liver, diabetes fatty liver, alcoholic fatty liver or Drug fatty liver.
10. the pharmaceutical composition described in application according to claim 1 or claim 2, it is characterised in that：The treatment
Fatty liver includes：1) make the content of free fatty in liver tend to be normal；2) reduce diffusivity fat vacuole in liver；3)
Improve liver function, liver function index (glutamic-pyruvic transaminase, glutamic-oxalacetic transaminease) is made to tend to be normal；4) liver weight is reduced；5) improve
Redox in liver is horizontal, and SOD activity, CAT activity and MDA contents is made to restore normal；6) blood fat is reduced.
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| CN110960553A (en) * | 2019-12-27 | 2020-04-07 | 武汉大学 | Application of malonic acid modified fullerene C70 in preparation of medicine for treating non-alcoholic fatty liver disease |
| CN111317745A (en) * | 2018-12-13 | 2020-06-23 | 中国科学院化学研究所 | Application of water-soluble fullerene structure in preparation of medicine for treating Parkinson's disease |
| CN115624624A (en) * | 2022-12-22 | 2023-01-20 | 南京智正医药科技有限公司 | Application of fullerene derivative in preparation of drugs for treating alcoholic liver disease |
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| CN110876757A (en) * | 2018-09-05 | 2020-03-13 | 中国科学院化学研究所 | Application of fullerene structure in preparation of medicine for treating atherosclerosis |
| CN111317745A (en) * | 2018-12-13 | 2020-06-23 | 中国科学院化学研究所 | Application of water-soluble fullerene structure in preparation of medicine for treating Parkinson's disease |
| CN111317745B (en) * | 2018-12-13 | 2021-09-07 | 中国科学院化学研究所 | Application of water-soluble fullerene structure in preparation of medicine for treating Parkinson's disease |
| CN110960553A (en) * | 2019-12-27 | 2020-04-07 | 武汉大学 | Application of malonic acid modified fullerene C70 in preparation of medicine for treating non-alcoholic fatty liver disease |
| CN110960553B (en) * | 2019-12-27 | 2023-10-03 | 武汉赛莱亚生物科技有限公司 | Application of malonic acid modified fullerene C70 in preparation of medicine for treating non-alcoholic fatty liver disease |
| CN115624624A (en) * | 2022-12-22 | 2023-01-20 | 南京智正医药科技有限公司 | Application of fullerene derivative in preparation of drugs for treating alcoholic liver disease |
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| WO2018113686A1 (en) | 2018-06-28 |
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