CN1274366C - Medicinal nano carbon microsphere and its application for preparing medicine to treat cancer - Google Patents
Medicinal nano carbon microsphere and its application for preparing medicine to treat cancer Download PDFInfo
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Classifications
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Inorganic Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a medicinal nanometer carbon sphere and an application thereof to the preparation of a medicine for treating cancer. The medicinal nanometer carbon sphere provided by the present invention and the antitumor medicine which is prepared by using the medicinal nanometer carbon sphere as a carrier and has biological guiding property can obviously enhance antitumor effect, lower the toxic and side effect of chemotherapeutic and radiotherapeutic medicines and decease the damage of the antitumor medicine to normal cells and the immune system of organisms to the maximum limit.
Description
Technical field
The present invention relates to medicinal nano carbon microsphere and the application in preparation treatment cancer drug thereof.Or rather, the present invention relates to a kind of medicinal nano carbon microsphere that has bio-guide character, is used as antitumor drug, a kind of is the antitumor drug with bio-guide character and preparation method thereof of carrier with the medicinal nano carbon microsphere, also relates to this medicinal nano carbon microsphere in the medicine of preparation treatment cancer drug, treatment cardiovascular and cerebrovascular disease and the application in the treatment rheumatic and rheumatoid diseases medicine.
Background technology
The whole world reaches 7,000,000 people because of malignant tumor death every year, about 2,000,000 people of Chinese annual neopathy, and tumor has become one of human main causes of death, and the prevention of cancer and treatment task are very arduous.The main means of treatment cancer are early discoverys at present, excision, but excision can not solve the problem of metastatic lesion.Owing to shift and often to cause postoperative recurrence, so generally after operation, all add with chemotherapy or radiotherapy in case spline is moved.But the effect of chemotherapy and radiation is also undesirable, reason is that the difference of the therapeutic dose of medicine and toxic dose is little, especially the hemopoietic function cell is extremely responsive to change, radiotherapy, causes serious systemic side effects in treatment inevitably, thereby can not life-time service or heavy dose of the use.
Ideal medicine is targetedly medicine to be directed to focal zone to greatest extent, makes the drug level in focal zone and normal cell district very big difference occur, thereby protects normal cell and tissue to preserve from effectively, Here it is targeted drug.Occurred the dosage form of lympha targeted medicine in this respect recently, as used, but domestic and foreign literature does not see that relevant is the report of the targeting preparation of carrier with the medicinal nano carbon microsphere with the targeting preparation of active carbon as carrier.The inventor is through studying for a long period of time and a large amount of test, and the result shows that medicinal nano carbon microsphere has bio-guide character, and tumor is had the obvious suppression effect, and has good medicine carrying effect, has finished the present invention on this basis.
Summary of the invention
First purpose of the present invention provides a kind of medicinal nano carbon microsphere that has bio-guide character, can be used as antitumor drug or carrier.
It is the antitumor drug with bio-guide character and preparation method thereof of carrier with the medicinal nano carbon microsphere that second purpose of the present invention provides a kind of.
The 3rd purpose of the present invention provides the application of medicinal nano carbon microsphere in preparation treatment cancer drug.
The 4th purpose of the present invention provides the application of medicinal nano carbon microsphere in preparation treatment cardiovascular and cerebrovascular diseases medicament.
A further object of the invention provides the application of medicinal nano carbon microsphere in preparation treatment rheumatism, rheumatoid disease medicine.
A kind of medicinal nano carbon microsphere that bio-guide character can be used as antitumor drug or carrier that has provided by the invention is characterized in that this medicinal nano carbon microsphere particle diameter is 2nm-1000nm, and wherein 90% diameter of particle is≤300nm, and its specific surface area is 100-3000M
2/ g, ash is lower than 8%, and loss on drying should be lower than 5%, and lead, cadmium, arsenic, mercury content are lower than 20ppm, and avirulence is answered in the inspection of undue toxicity's inspection technique; The microbial limit test inspection always contains the every gram of bacterium number should be lower than 100.
The raw material that is used to prepare this medicinal nano carbon microsphere can be selected from nano-carbon material, the VXC72 nano carbon microsphere that for example commercially available U.S.'s Cabot (Carbot) company produces, and its characteristic is as shown in table 1:
Table 1
| Performance project | Unit | Index |
| Specific surface area | M 2/g | 254 |
| Oil factor | ML/100g | 192/174 |
| Tinting strength, tinting power | ％ITRB | 87 |
| Particle diameter | nm | 30 |
| Ash | ％ | 1.0 |
| Loss on drying | ％ | 1.0 |
The preparation method of medicinal nano carbon microsphere of the present invention is as follows:
With commercially available medicinal nano carbon microsphere 0.1g, add 0.1N hydrochloric acid 5mL, immersion treatment 8 hours, add water 50mL, filter, being washed to PH repeatedly is 6, add 0.1N sodium hydroxide 5mL, handled 8 hours, and filtered, being washed to PH is 8-9, add 0.1N hydrochloric acid 5mL, filter, drying is until the medicinal nano carbon microsphere that obtains to conform to quality requirements.
The invention provides a kind of is the antitumor drug with bio-guide character (being called for short the A preparation) of carrier with the medicinal nano carbon microsphere, it is characterized in that its composition and proportioning are as follows:
Medicinal nano carbon microsphere 5-100mg
Directed agents 0-10mg
Suspending agent 0-30mg
Surfactant 0-15mg
Excipient 0-500mg
Water is an amount of.
Above-mentioned antitumor drug, its feature are that also the raw material for preparing medicinal nano carbon microsphere is selected from nano-carbon material, for example VXC-72; Directed agents is selected from folic acid and its esters, as calcium folinate; Suspending agent is selected from polyvinylpyrrolidone, arabic gum, tragacanth, polyvinyl alcohol Sodium Tvlose, hydroxypropyl emthylcellulose etc., is preferably polyvinylpyrrolidone; Surfactant is selected from tween, polyoxyethylene castor oil, Bo Luoshamu etc., is preferably Bo Luoshamu; Excipient is selected from serum albumin or gamma globulin.
Above-mentioned preparing anti-tumor medicine method comprises the steps:
(1) prepares the medicinal nano carbon microsphere that conforms to quality requirements;
(2) add suspending agent and/or surfactant by proportioning;
(3) add directed agents by proportioning, sonic oscillation was handled 30～60 minutes, autoclaving 30～60 minutes, and packing, embedding, autoclaving 45 minutes obtains the formulation in liquid form finished product;
(4) add excipient by proportioning, lyophilization promptly gets lyophilized powder type finished product under aseptic condition.
It is the antitumor drug with bio-guide character (being called for short the B preparation) of carrier with the medicinal nano carbon microsphere that the present invention also provides another kind of, it is characterized in that its composition and proportioning are as follows:
Medicinal nano carbon microsphere 5-100mg
Directed agents 0-20mg
Anti-tumor active ingredient 1-100mg
Suspending agent 0-30mg
Surfactant 0-15mg
Excipient 0-500mg
Water is an amount of.
Above-mentioned antitumor drug, its feature are that also the raw material of medicinal nano carbon microsphere is selected from nano-carbon material, as VXC72; Directed agents is selected from folic acid and its esters, as calcium folinate; Anti-tumor active ingredient is selected from anti-tumor chemotherapeutic medicine, antitumor radiotherapy medicine, the material, anti-tumour antibody or the incomplete antibody class that suppress tumor-blood-vessel growth, interferon or anticancer polypeptide class etc., is preferably anti-tumor chemotherapeutic and radiotherapy medicine; Suspending agent is selected from polyvinylpyrrolidone, arabic gum, tragacanth, polyvinyl alcohol Sodium Tvlose, hydroxypropyl emthylcellulose etc., is preferably polyvinylpyrrolidone; Surfactant is selected from tween, polyoxyethylene castor oil, Bo Luoshamu etc., is preferably Bo Luoshamu; Excipient is selected from serum albumin or gamma globulin.
Above-mentioned preparing anti-tumor medicine method is characterized in that this method comprises the steps:
(1) prepare the medicinal nano carbon microsphere that conforms to quality requirements:
(2) add suspending agent and/or surfactant and anti-tumor active ingredient, mix homogeneously by proportioning;
(3) add directed agents by proportioning, sonic oscillation was handled 30～60 minutes, autoclaving 30～60 minutes, and packing, embedding, autoclaving 45 minutes obtains the formulation in liquid form finished product;
(4) add excipient by proportioning, lyophilization gets product under aseptic condition.
The present invention also provides the application of this medicinal nano carbon microsphere in preparation treatment cancer drug.
The present invention also provides the application of this medicinal nano carbon microsphere in preparation treatment cardiovascular and cerebrovascular diseases medicament.
The present invention also provides the application of this medicinal nano carbon microsphere in preparation treatment rheumatism, rheumatoid disease medicine.
For back two kinds of application, employed preparation is not for adsorbing the medicinal nano carbon microsphere of anti-tumor active ingredient, the same anticancer preparation of its dosage and principle, it is to assemble to arteriosclerosis district and rheumatic and rheumatoid focus orientation by reticuloendothelial system, peels off, eliminates focus by phagocytosis then.
The route of administration of preparation of the present invention is as follows: preparation of the present invention needs just can work by blood flow and reticuloendothelial system, anyly blood flow can be entered directly or indirectly or lymphoid route of administration all is suitable for, be preferably intravenously administrable and intraperitoneal administration, in addition can muscle administration and mucosa delivery; Because the M cell in the intestinal wall has the ability of pinocytosis less than the 100nm microgranule, so preparation of the present invention also can be taken orally.Dosage is decided on the kind and the administering mode of contained medicine, the recommended dose when vein or muscle administration: each consumption of being grown up (referring to medicinal nano carbon microsphere content) 10-80mg, every other day once or weekly twice, three month be a course of treatment; Intraperitoneal administration dosage rises to 5000mg; Because preparation toxicity of the present invention is very little, oral dose can according to the state of an illness use the 0.1-5 gram/time.More than be the dosage of medicinal nano carbon microsphere, contained dose all need be lower than the routine dose of clinical use under the situation of its loading anti-tumor active ingredient, looks the state of an illness and grasp flexibly, is generally 1/10～2/10.
Beneficial effect to medicinal nano carbon microsphere and application thereof is described as follows below:
Animal test results shows that particle diameter is that the medicinal nano carbon microsphere of 2-300nm has good bio-guide character, and its guide effect is to the motion of inflammation district, gathering and fixing the realization by the phagocyte in the reticuloendothelial system.This tropism can greatly be strengthened by loading cancer cell multiplication hobby material.Therefore medicinal nano carbon club sees through blood vessel wall and automatically to the focal zone enrichment of tumor under immune effect.Cancerous cell is because its differentiation degree is lower than normal cell, so have stronger phagocytic activity, after medicinal nano carbon microsphere is engulfed by cancerous cell, the metabolism multilated of cancerous cell and cause death, so medicinal nano carbon microsphere itself has the effect that suppresses tumor growth and kill tumor cell.If be carrier absorption and carrier band anti-tumor active ingredient with the medicinal nano carbon microsphere then more strengthened killing the effect of cancerous cell, thereby prepare various antineoplastic targeting medicines, make between tumor blood capillary inside and the tumor cell drug level in the matter reach dozens or even hundreds of times of conventional treatments, greatly strengthen antitumor curative effect, reduced the toxic and side effects of chemotherapy, radiotherapy medicine.Therefore on the basis of using medicinal nano carbon microsphere, the dosage of routine clinical chemotherapy and radiation can drop to the 10-20% of former using dosage, but reach on the contrary than the better therapeutic effect of routine dose, and can reduce usually the infringement normal cell and the immune side effect of being seenly putting, being difficult to avoid in the chemotherapy to greatest extent.Result of study also shows in addition, medicinal nano carbon microsphere of the present invention is atherosis to artery, coronary heart disease, cerebral thrombosis all have prevention effect, infectious disease such as rheumatic and rheumatoid also there is obvious therapeutic effect, its mechanism is because all focal zones have inflammation, the tropism of oriented these focal zone motions of medicinal nano carbon microsphere, looking medicinal nano carbon microsphere in the phagocyte of focal zone is foreign body, inspires and engulfs characteristic, then little by little peels off focus in the process of engulfing.
Below by animal experiment beneficial effect of the present invention is described:
(1) acute toxicity test of medicinal nano carbon microsphere:
1, antitumor agent: the VXC72 that produces with U.S. Carbot company is a raw material preparation medicinal nano carbon microsphere earlier, does not add anti-tumor active ingredient, obtains the medicinal nano carbon microsphere preparation.
2, experimental animal: the CD-1 mice is provided by BJ Univ Hospital's animal center.
3, dosage and administering mode: get and clean the male CD-1 mice of level, the 18-22 gram, totally 60, be divided into 6 groups, 10 every group, under aseptic condition,, 2 times weekly, 0.1ml//time, calculate integral dose by each group dosage tail vein injection administration.
Result of the test is as shown in table 2
Table 2
| Number of animals | Product A dosage (mg/KG) | Death toll (n) | Dead % | The dosage logarithm | Probability unit | |
| 1 | 10 | 160 | 1 | 10 | 2.204 | 3.720 |
| 2 | 10 | 180 | 1 | 10 | 2.255 | 3.720 |
| 3 | 10 | 200 | 2 | 20 | 2.301 | 4.160 |
| 4 | 10 | 220 | 4 | 40 | 2.342 | 4.475 |
| 5 | 10 | 240 | 5 | 50 | 2.380 | 5.000 |
| 6 | 10 | 260 | 5 | 50 | 2.415 | 5.000 |
Regression equation is: Y=-12.6303+7.3487X, (r=0.9586)
When a=0.01, r is 0.9170, (wherein Y is that probability unit adds the value after 5, and X is the logarithm log x of dosage)
Calculating LD50 is 250.6801mg/kg
Confidence interval during confidence coefficient a=0.05 is: 201.4321≤LD50≤311.9688,0.0950
The result shows that medicinal nano carbon microsphere of the present invention is 250.68mg/Kg to the acute toxicity LD50 of mice, and this toxicity that shows preparation of the present invention is lower, as safe as a house.
(2) inhibition test of medicinal nano carbon microsphere (A preparation):
The purpose of this test is to estimate the tumor-inhibiting action of medicine to the S180 tumor-bearing mice.
Material and method
Tried thing
Being tried name claims: S2
Being tried thing originates: Velgene company
State when being tried thing and receiving: peace is cutd open the bottle encapsulation
Date received: on October 26th, 2004
Date of test: on November 08,26 days to 2004 October in 2004
Laboratory animal: laboratory animal is the CD mice, the SPF-VAF level, and totally 70, male, 18g-22g is provided by our department, the quality certification number: SCXK (capital) 2002-0001.
Feeding environment: raise in SPF level Animal Lab., temperature is 25 ℃ ± 2 ℃, and relative humidity is 55% ± 15%.
The quality certification number: SYXK (capital) 2002-0002.
Feedstuff: mice growth special feed, provide by Beijing section Australia feed corporation,Ltd that pulls together,
The quality certification number: moving (2000) No. 015 of capital.
Animal grouping and group technology
According to inoculated tumour time order and function and body weight size, carry out random packet, being divided into is 5 groups, 14 every group.
Negative control: the sterile saline group (Hui Da of Datong District pharmaceutcal corporation, Ltd, product batch number: 0311081, specification: 10ml: 90mg)
Positive control: cyclophosphamide group (specification: 0.2g/ props up for Hengrui Medicine Co., Ltd., Jiangsu Prov., lot number 04070821)
Low dose group: 1mg/kg body weight group
Middle dosage group: 2mg/kg body weight group
High dose group: 4mg/kg body weight group
Experimental technique:
1, the preparation of inoculation tumor liquid: tumor-bearing mice is dissected by the sterile working, the numeration of microscopically cell, and being prepared into concentration is 2 * 107 cell/ml, 20ml is used for inoculation altogether.
2, tumor inoculation: sterile working, axil subcutaneous vaccination tumor liquid 0.2ml/ only, i.e. 4 * 106 cell/mices.
3, medication: except that positive controls, respectively organize in inoculation and carried out the tail vein injection administration in the 1st day, the 3rd day, the 6th day, the 8th day, the 10th day; Positive controls lumbar injection ring phosphamidon is pressed the dosage of 30mg/kg, in inoculation administration in the 1st day, the 3rd day, the 6th day, the 8th day, the 10th day.
Detect index:
1, observes animal health condition and death condition every day.
Claim the weight of animals and tumor heavy when 2, experiment finishes.
3, cut open the inspection animal, observe the main organs pathological change.
Data statistics:
The curative effect of solid tumor heavily suppresses percentage rate with tumor and represents.
The heavy suppression ratio %=(1-T/C) * 100% of tumor
Tumour inhibiting rate is greater than 40%, and handle when there were significant differences by statistics, and thinking has the symptom of a trend.
Statistical procedures adopts SPSS for windows to analyze.
Surpass 20% if administration group Mus is dead during the treatment, or average weight decline surpasses 15%, the toxic reaction of expression medicine.
The result
1, medicine sees Table 3 to the influence of the weight of animals and survival state
Table 3 medicine is to the influence of the weight of animals and survival state
| Group | The initial body weight of animal (gram) | The weight of animals (gram) when experiment finishes | Mortality rate % |
| Dosage group in the negative control group positive controls low dose group | 21.8±1.01 21.3±0.98 21.0±1.23 21.6±1.11 | 27.2±3.74 29.7±1.45 28.5±2.88 29.3±1.83 | 14.3 - 5.1 6.4 |
| High dose group | 21.2±1.17 | 27.9±5.08 | 7.4 |
2, medicine sees Table 4 to the tumor-inhibiting action of tumor-bearing mice
Table 4 medicine is to the tumor-inhibiting action of tumor-bearing mice
| Group | Tumor heavy (gram) | Tumour inhibiting rate % |
| Dosage group in the negative control group positive controls low dose group | 1.23±0.28 0.60±0.23 ** 0.31±0.22 ** 0.69±0.32 ** | - 51.3 75.1 44.2 |
| High dose group | 0.65±0.55 ** | 47.3 |
*P＜0.01 is compared with negative control group, has extremely to show difference.
3, the main organs general pathology is observed
High, medium and low dosage group experimental result shows that each internal organs shape of liver, quality, color etc. are normal.
Conclusion
Under this experiment condition, treatment low dose group, middle dosage group and high dose group all have tumor-inhibiting action, and be the highest with the low dose group tumour inhibiting rate, thinks that this medicine has the Seedling head; And high, medium and low dosage group experimental result shows that this drug toxicity is less.
(3) the external test that kills and wounds cancerous cell of medicinal nano carbon microsphere:
Use kidney cancer cell R11, in RPMI-1640, cultivate, A preparation ratio with the 2mg/50ml culture fluid under aseptic condition is added the variation of observing the R11 cell in the Tissue Culture Flask, the result who observes shows, the same day, cancerous cell just stopped growing, next day, cancerous cell was engulfed a large amount of microgranules, began swelling fracture then.Equally distributed microgranule is enriched to cell interior (almost can't see microgranule in the contrast culture bottle background) in culture bottle, illustrate that microgranule initiatively engulfed by cancerous cell, cell quantity begins to reduce, be dissolved into ghost fully through a pericyte, this proof is after cancerous cell initiatively engulfs microgranule, cellular metabolism multilated and cause cell death.
The specific embodiment
The following examples are only in order to further specify the present invention, rather than limit the scope of the invention.
Embodiment 1
The preparation of medicinal nano carbon microsphere:
Select the U.S. VXC72 of CARBOT company medicinal nano carbon microsphere 0.1g for use, add 0.1N hydrochloric acid 5mL, immersion treatment 8 hours, add water 50mL, filter, be washed to PH6 repeatedly, add 0.1N sodium hydroxide 5mL, handled 8 hours, filter, be washed to PH8-9, add 0.1N hydrochloric acid (pact) 5mL, be washed to PH=6-7, filter, drying obtains the finished product medicinal nano carbon microsphere.
Drying is weighed as 0.08 gram, and yield is 80%.Meet the requirement of medicinal nano carbon microsphere of the present invention after testing.
Embodiment 2
Get the medicinal nano carbon microsphere 40mg that embodiment 1 makes, add entry 35mL, stir, add the about 0.5g of surfactant Tween-80, stir, add polyvinylpyrrolidone K30 suspending agent 2g; Stir, add the water standardize solution to 50mL, sonic oscillation 30 minutes stopped 5 minutes, and vibration 4 minutes, messenger drug fully disperseed to become uniform nanometer suspension liquid with nano carbon microsphere, packing, embedding, autoclaving 45 minutes, and lyophilization promptly gets lyophilized powder.
Embodiment 3
Get the medicinal nano carbon microsphere 40mg that embodiment 1 makes, add entry 35mL, stir, add the about 0.5g of surfactant Tween-80, stir, add polyvinylpyrrolidone K30 suspending agent 2g and add 5-Fu 3mg, stir, add the water standardize solution to 50mL, sonic oscillation 15 minutes stopped 5 minutes, vibrated again 15 minutes, messenger drug fully disperses to become uniform nanometer suspension liquid with nano carbon microsphere, and packing, embedding, autoclaving 45 minutes obtain the finished product of formulation in liquid form.
Embodiment 4
Get the medicinal nano carbon microsphere 40mg that embodiment 1 makes, add entry 35mL, stir, add the about 0.5g of surfactant Tween-80, stir, add polyvinylpyrrolidone K30 suspending agent 2g; Add excipient serum albumin 2mg, stir, add the water standardize solution to 50mL, sonic oscillation 15 minutes stopped 5 minutes, vibrated 15 minutes again, and messenger drug fully disperses to become uniform nanometer suspension liquid with nano carbon microsphere, and lyophilization promptly gets the lyophilized powder finished product.
Embodiment 5
Get the medicinal nano carbon microsphere 40mg that embodiment 1 makes, put in the bottle,suction, behind the evacuation, inject 1% calcium folinate aqueous solution 2ml.The agitator shake well adds entry 35mL again in the solution, stir, and adds the about 0.5g of surfactant Tween-80, stirs, and adds polyvinylpyrrolidone K30 suspending agent 2g; Add excipient serum albumin 2mg, stir, add the water standardize solution to 50mL, sonic oscillation 5 minutes stopped 5 minutes, vibrated 4 minutes again, messenger drug fully disperses to become uniform nanometer suspension liquid with nano carbon microsphere, packing, embedding, autoclaving 45 minutes, and lyophilization promptly gets the lyophilized powder finished product.
Claims (1)
1, a kind of have the application of medicinal nano carbon microsphere in preparation treatment cancer drug that bio-guide character can be used as antitumor drug, it is characterized in that this medicinal nano carbon microsphere is an active ingredient, its particle diameter is 2nm-1000nm, wherein 90% diameter of particle is≤300nm, and its specific surface area is 100-3000M
2/ g, ash is lower than 8%, and loss on drying should be lower than 5%, and lead, cadmium, arsenic, mercury content are lower than 20ppm, and avirulence is answered in the inspection of undue toxicity's inspection technique; The microbial limit test inspection always contains the every gram of bacterium number should be lower than 100.
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| CNB2004100971505A CN1274366C (en) | 2004-12-13 | 2004-12-13 | Medicinal nano carbon microsphere and its application for preparing medicine to treat cancer |
| PCT/CN2005/002112 WO2006063506A1 (en) | 2004-12-13 | 2005-12-07 | Utilization for carbon nanosphere in anti-cancer medicine |
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| US20100215960A1 (en) | 2009-02-24 | 2010-08-26 | Toyota Motor Engineering & Manufacturing North America, Inc. | Hollow carbon spheres |
| CN101791320B (en) * | 2010-04-16 | 2013-01-16 | 汪中 | Application of nano carbon particles in preparing external medicament for curing haemorrhoids and external medicament |
| CN102370989B (en) * | 2010-08-19 | 2013-05-29 | 逢甲大学 | Medicinal composition for the treatment of the urinary system |
| CN103043646B (en) * | 2012-12-21 | 2014-06-04 | 浙江大学 | Method for preparing small solid carbon ball and carbon ball prepared thereby |
| CN112494655A (en) * | 2020-12-24 | 2021-03-16 | 中南大学湘雅医院 | Nano carbon-drug composite system and preparation method and application thereof |
| CN113415798B (en) * | 2021-05-12 | 2023-02-24 | 江西农业大学 | Preparation method of phosphorus-doped microporous, mesoporous and macroporous coexisting grade pore structure carbon nanospheres |
| CN116139169A (en) * | 2021-11-19 | 2023-05-23 | 北京大学 | Application and drug or product of micro-nano carbon particles in inhibiting oxidative stress response to prevent and treat related diseases |
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