CN109481464A - A kind of injection fullerene emulsion and preparation method thereof - Google Patents
A kind of injection fullerene emulsion and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of injection fullerene emulsions and preparation method thereof, it includes weight percent fullerene oil 15-50%, emulsifier 4-17%, stabilizer 0.3-1%, excipient 2-9% and surplus water for injection, and do not include solvent or cosolvent, the fullerene emulsion is the oil-in-water emulsion stable in pH7.3-7.4, and the emulsion safety and stability, bioavilability are high.
Description
Technical field
The present invention relates to field of medicaments, more particularly, to a kind of injection fullerene emulsion and preparation method thereof.
Background technique
Series Molecules with caged Carbon Cluster structure are collectively referred to as fullerene, are except graphite, diamond and nothing
Another allotrope of carbon except sizing carbon.Fullerene mainly includes empty fullerene, embedded fullerene, fullerene
Derivative and heterocycle fullerene etc..
Have in the prior art by fullerene C60It is dissolved in the report studied in olive oil, it is found that it can not influence physiology
Free radical is removed in the case where performance and extends the life of lab mice, but is dissolved in the fullerene C of olive oil60Into animal body
After interior, digestion and absorbing state are not ideal, meanwhile, after a large amount of grease intake in vivo, internal intestinal flora can be produced
Raw application, some three-high patients may aggravate the state of an illness because of many greases of sauce two was taken in.Therefore directly taking oils will affect medicine
The performance of object effect.Patent WO2013/0251/80A1 mixes fullerene powder with vegetable oil, by ball milling, centrifugation, filtering
Afterwards, fullerene vegetable oil is obtained, treats disease by the way of directly drinking fullerene vegetable oil.Oral preparation generally there are
The low problem of bioavilability, therefore by medicine preparation at the form of injectable, it is stronger in particular for grade malignancies such as cancers
Illness, can preferably play drug effect, treatment disease CN104983676A discloses a kind of fullerene injection, passes through injection
Mode fullerene ingredient is directly delivered to Hematological System of Professional Workers, make one body can absorb faster more fullerenes at
Point.Fullerene injection is by the sterile fuller olefinic carbon 60 .01-8% of weight percent composition, Cremophor EL 45-
60%, dehydrated alcohol 35-50% make solvent with Cremophor EL and dehydrated alcohol, fullerene can be made sufficiently to dissolve.
But the polyoxyethylene of its in the patent can play the effect of increase-volume for castor oil as emulsifier, polyoxyethylene is for castor-oil plant
Oily sensitization rate is very high, and sensitization mechanism there is no explanation, and the common igelite infusion apparatus interaction of meeting at present, leaches
Dioctyl phthalate therein, causes toxicity；Achieve the purpose that solubilising using ethyl alcohol is added, and much solubilizer can cause
The change and tissue damage of biomembrane form；States Pharmacopoeia specifications use amount of alcohol maximum 12%, can cause drug using excessive ethyl alcohol
Overweight middle reprecipitation is discharged, drug absorption utilization rate is influenced.
In order to improve the bioavilability and safety of fullerene, the present invention has selected a kind of without containing solvent or cosolvent
Injection fullerene emulsion is not investigated also.
Summary of the invention
In order to overcome the above technical problems, it the purpose of the present invention is to provide a kind of injection fullerene emulsion, greatly mentions
High fullerene bioavilability, the long-acting circulation of enhancing fullerene in vivo increase targeting effect.
Another object of the present invention is to the preparation method of injection fullerene emulsion, obtained injection fullerene emulsion
With higher solubility.
Inventor has found in preparation injection fullerene emulsion that homogeneous all obtains in any case for fullerene, oil for injection, emulsifier
Less than homogeneous latex emulsion, and suspension is presented always.It is prepared again with emulsifier homogeneous after fullerene oil is made in fullerene in advance
Obtained lotion can overcome drawbacks described above.
The invention is realized by the following technical scheme:
A kind of injection fullerene emulsion includes weight percent fullerene oil 15-50%, emulsifier 4-17%, stablizes
Agent 0.3-1%, excipient 2-9% and surplus water for injection, and do not include solvent or cosolvent, the fullerene emulsion is
PH7.3-7.4 stable oil-in-water emulsion.
Injection fullerene emulsion of the present invention is oil-in-water type injection fullerene emulsion, the grain of the emulsion droplets
Diameter 50-150nm.
Fullerene oil of the present invention is that fullerene is dissolved into oil for injection, and the solubility is 1-10mg/
Ml, further preferred fullerene concentration are 2-7mg/ml.
Preferably, in above-mentioned technical proposal, the fullerene is empty fullerene and/or metal fullerene.Including but
It is not limited to fullerene C2n、M@C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2nAnd MxA3-xN@C2nIn
It is any, wherein M and A is metallic element, and the M and A are selected from any one in Sc, Y and lanthanide element；30
≤n≤60；0≤x≤3.
The further preferably described fullerene selects C60、C70、C76、C84One or more of mixtures.
The oil for injection be vegetable oil, be including but not limited to olive oil, soybean oil, prinsepia utilis royle oil, linseed oil,
Sunflower oil, SIMMONDSIA CHINENSIS SEED OIL, peanut oil, tea oil, tea oil, rose hip oil, macadamia nut oil, avocado oil, castor oil, maize germ and
At least one of corn oil.Further preferred soybean oil, olive oil, prinsepia utilis royle oil, tea oil.More preferable soybean oil, soybean oil remove
It is high to fullerene solubility, contain a large amount of unsaturated fatty acids simultaneously, is more suitable for injecting.
Further preferably, fullerene oil dosage of the present invention accounts for injection fullerene emulsion 15-40%.
Emulsifier of the present invention selects that emulsifying capacity is strong, high temperature resistant, the auxiliary material easily stored according to fullerene feature.It is excellent
Selecting emulsifier includes but is not limited to Labraso, ethyl oleate, soybean lecithin, egg yolk lecithin, phosphatide
It is phatidylcholine, poloxamer-188, one or more of in 15-hydroxy polyethylene glycol stearate.The emulsifier accounts for injection
With the 4-17% of fullerene emulsion, preferred emulsifier dosage accounts for injection fullerene emulsion 5-13%, optimum emulsification agent dosage 5-
7%.Inventor has found to be applied alone a kind of emulsifier effect unobvious in a large amount of screening process, when two kinds of emulsifiers of selection share
Cost can not only be reduced and emulsifying capacity is strong, toxicity is low, it is often more important that stability increases.It is preferred that poloxamer-188
It is shared with 15-hydroxy polyethylene glycol stearate.The weight of the poloxamer-188 and 15-hydroxy polyethylene glycol stearate
Amount is than being (0.6-4): 1, further preferred (1-1.6): 1.
Stabilizer of the present invention includes but is not limited to sodium citrate, sodium alginate, dodecyl sodium sulfate, preferably lemon
Sour sodium.The sodium citrate is safe and non-toxic, mobility is good, into after human body can fast degradation drain fastly.The stability is used
Amount is the 0.3-1% of injection fullerene emulsion.
Excipient of the present invention is acceptable additive in injection, including water-soluble excipient such as osmotic pressure is adjusted
Agent, pH adjusting agent or other biological compatible substances and oiliness excipient such as antioxidant etc..
Osmotic pressure regulator of the present invention include but is not limited to glucose, glycerol, sorbierite, it is a kind of in mannitol or
More than.The osmotic pressure regulator dosage accounts for the 2-8% of injection fullerene lotion.It is preferred that 3-6%.
Antioxidant of the present invention includes but is not limited to sulphite, ascorbic acid, propylgallate, tocopherol
In it is one or more of.The antioxidant dosage accounts for the 0.01-0.1% of injection fullerene lotion.
PH adjusting agent of the present invention includes but is not limited to select hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, sodium bicarbonate
In it is one or more of.
Biocompatible substance of the present invention includes but is not limited to albumin, sorbierite, glycine, dextran etc..
The invention also discloses the preparation methods of injection fullerene emulsion, include the following steps:
(1) fullerene oil is prepared:
(2) oily phase is prepared:
(3) water phase is prepared:
(4) prepared by oil-in-water type fullerene emulsion:
It after being sufficiently mixed at fullerene end and oil for injection uniformly in above-mentioned steps (1), is placed in ball mill, ultrasound is stirred
It mixes, heat, dissolve fullerene sufficiently in oil for injection, fullerene oil is obtained by filtration.
Further preferably, fullerene powder is carried out ball milling and refines 0.05-1 μm by step (1), then by the fullerene after refinement
Powder is mixed with oil for injection, is placed in ball mill 500-1000 revs/min, ball milling 8-20h, obtains the suspension of fullerene oil
Liquid, then fullerene oil suspension is heated to 40-60 DEG C, nitrogen protection, after stirring 12-72h, centrifugation, filtering obtain fullerene
Oil solution.
Further preferably, it after fullerene powder and oil for injection are sufficiently mixed uniformly by step (1), is placed in ball mill,
700 revs/min, ball milling 8h, fullerene oil suspension is obtained, then fullerene oil suspension is heated to 40 DEG C of ultrasonic agitation heating
12-24h, centrifugation, filtering, obtains fullerene oil solution.
Emulsifier, fullerene oil are preheated in above-mentioned steps (2), addition oiliness excipient, which is placed in dispersion machine, to be stirred
It is even to obtain oily phase.
Further preferably, emulsifier, fullerene oil are preheated 55-70 DEG C by step (2), and oiliness excipient is added and is placed in point
Machine is dissipated to be uniformly dispersed with the revolving speed stirring 2-10min of 5000-10000rmp to get oily phase.
Further preferably, step (2) dispersing speed 7000rmp stirs 5min.
Step (3) of the present invention, by stabilizer, aqueous vehicle, water for injection, preheating, which is placed in dispersion machine, is stirred
It is uniform to obtain water phase.
Further preferably, stabilizer, aqueous vehicle, water for injection are preheated 55-70 DEG C, are placed in dispersion machine by step (3)
In be uniformly dispersed with the revolving speed of 5000-10000rmp stirring 2-10min to get water phase.
Further preferably, step (3) dispersing speed 7000rmp stirs 5min.
Oil is mutually slowly added into water phase to be placed in dispersion machine and be dispersed with stirring uniformly by step (4) of the present invention, micro- to penetrate
Stream is high-pressure homogeneous to get oil-in-water type fullerene emulsion.
Further preferred step (4) at 60-80 DEG C by oil be mutually slowly added into dispersion 7000-10000rmp in water phase,
5-15min dispersion and emulsion obtains slightly cream, is cooled to room temperature, puts into microjet or high pressure homogenizer naturally to thick newborn temperature,
Under pressure 50-60Mpa, homogeneous 5-6 times is 140-150nm or emulsion partial size 50-100nm is made in microjet until emulsion partial size,
Up to smart cream, pH to 7.3-7.4 is adjusted, water for injection is supplied, packing, nitrogen charging, sterilizing.
What currently preferred homogenization pressure and homogenization cycles were screened according to emulsion partial size and stability.Pressure is got over
Greatly, homogenization cycles are more, and emulsion partial size is smaller, more uniform, emulsion is more stable；But homogenization cycles are excessive, after emulsion partial size is too small,
Emulsion droplet contact area becomes larger, and emulsion droplet ability of aggregation is caused to enhance, and reduces the stability of emulsion instead.Homogeneous of the present invention obtains 140-
150nm emulsion stability is good, does not find clustering phenomena.The present invention uses microjet can be in order to which smaller partial size emulsion is made
Solve the problems, such as the small emulsion droplet aggregation of partial size, microjet is in more stable state by emulsion droplet.
The present invention also provides effect of the injection fullerene emulsion in preparation tumor.Especially making
Application in the drug of standby treatment bone marrow suppression.
Beneficial effect
In order to preferably describe beneficial effects of the present invention, illustrated by following test examples
Test example one, the screening of oil for injection
1, emulsifier selects
Method: it after 1 fullerene powder of table and grease type auxiliary material are sufficiently mixed uniformly, is placed in ball mill, 700 revs/min
Then 40 DEG C of ultrasonic agitations of mixture are heated 12h, dissolve fullerene sufficiently in oil for injection, finally mistake by clock, ball milling 8h
Filter obtains fullerene oil.
As a result: soybean oil shown in table 1, olive oil, prinsepia utilis royle oil, tea oil are relatively good to the solubility of various fullerenes, more
It is preferred that soybean oil is more suitable for oil for injection wherein containing a large amount of unsaturated fatty acids.
Table 1: fullerene and vegetable oil intermiscibility screen
The screening experiment of two emulsifier of test example
Method: emulsifier selection principle: emulsifying capacity is strong, high temperature resistant, the auxiliary material easily stored, non-toxic and safe.Select table 2
Middle emulsifier, investigates the storage condition of emulsifier, and emulsifying capacity is nontoxic (sensitization, haemolysis)
Table 2: Selection of Emulsifier
As a result: as can be seen from Table 2, selection cost is relatively low, emulsifying capacity is strong, toxicity is low poloxamer-188 and 15- hydroxyl
Base stearic acid macrogol ester is as preferred.
2, emulsifier shares and matches screening
Method: 3 auxiliary material of table prepares oil-in-water fullerene emulsion, screens prescription oil 20g, prepares concentration 1mg/ml.
Table 3: emulsifier and proportion screening
As a result: as seen from Table 3, emulsifier is capable of forming uniform emulsion within the scope of 5-6.5%, but sample 7,8 is applied alone
Although HS-15 or poloxamer dosage reach 5%, emulsifying capacity is still weaker, and emulsion is unevenly layered, so selection two
Kind or two or more emulsifier prepare emulsion.HS-15 and poloxamer are shared solution emulsifying capacity by sample 3,5-6,
And there is synergistic effect.Inventor investigates the proportion situation of the two again and occupies the ratio of emulsion, when emulsifier works as poloxamer
It is (0.6-1.5): 1 stable emulsion being prepared with HS-15 ratio, it is uniformly not stratified.Industrialization considers that HS-15 price is high
In poloxamer, HS-15 dosage is more excellent prescription, further preferred poloxamer and HS-15 ratio less under the conditions of being prepared into cream
Example is (1-1.5): 1.
The screening of three stabilizer of test example
Table 4: stabilizer screening
As a result: by table 4, stabilizer select safe and non-toxic, mobility is good, into capableing of fast degradation excretion after human body
Sodium citrate.
The selection of four technological parameter of test example
Method: according to the prescription and preparation method of embodiment 1, parameter such as table 5-7.
Table 5: the screening of emulsifying temperature:
Ke value is centrifugation steadiness parameter, and the smaller expression emulsion of Ke value is more stable.As shown in Table 5, emulsion preparation temperature is 60
DEG C when centrifugation steadiness parameter it is minimum, emulsion stability is best.
High pressure homogenizer plays the role of emulsifying homogeneous, therefore emulsion prepared by pressure difference during preparing emulsion
Partial size is different, influences the stability of final emulsion, screens to homogenization pressure, after homogeneous 5 times, detects emulsion partial size.
Table 6: high-pressure homogeneous pressure screening
Obtained by table 6: emulsion partial size is without significant difference at 60MPa and 50MPa for homogenizer pressure, with inexpensive principle,
Matter pressure is 50MPa.
How much the homogeneous at uniform pressure 50Mpa, homogenization cycles equally influence the size of emulsion partial size, and homogenization cycles are got over
More, emulsion partial size is smaller, more uniform, emulsion is more stable；But homogenization cycles are excessive, after emulsion partial size is too small, emulsion droplet contact area
Become larger, emulsion droplet ability of aggregation is caused to enhance, reduces the stability of emulsion instead.
Table 7: high-pressure homogeneous number screening
Obtained by table 7: homogenization cycles are in 5 and 6 partial sizes without significant difference, and with inexpensive principle, homogenization cycles, which are selected 5 times, is
Prepare number.
Test example fiveChemotherapeutic protection effect of fullerene emulsion living body level
Animal model: 4-5 weeks ICR mouse is randomly divided into 4 groups, and every group 6, drug A group: CTX+1mg/ml emulsion for injection
Group, tail vein injection, each 100ul；Drug B group: CTX+5mg/ml fullerene oil group, gastric infusion, each 100ul；Control
Group C: physiological saline (Saline), cyclophosphamide (CTX) experimental group D.(H22 is thin for 106 murine hepatocarcinoma cells of mouse hypodermic inoculation
Born of the same parents), after inoculation 5-7 days, when diameter of tumor reaches 5mm or so, tested.CTX dosage is 60mg/kg mouse weight.In
Start to be administered within the 7th day after tumor inoculation, as first day for starting to test, once a day, and continuous 5 days, respectively at the 4th day,
7th day, the tenth day, fortnight and the 17th day took blood (20 μ l) from mouse orbit, were detected with haemocyte automatic analyzer
Blood routine, neutralizing the relevant main indicator of bone marrow suppression is white blood cell count(WBC) (WBC), red blood cell count(RBC) (RBC), blood platelet meter
Number (PLT), hemoglobinometry (HGB).Corresponding testing result is as shown in table 8, from table 8 it can be seen that: with blank control group phase
Than index relevant to bone marrow suppression in the mouse in cyclophosphamide (CTX) experimental group: leucocyte, red blood cell, blood platelet, blood
Lactoferrin suffers from different degrees of reduction in Mice Body, wherein the reduction with leucocyte is the most obvious；And CTX+ fullerene
Mouse in emulsion for injection experimental group, due to the protective effect of fullerene, leucocyte, red blood cell, blood platelet, hemoglobin
Amount is suffered from compared to cyclophosphamide (CTX) experimental group significantly to be improved, and with the extension of time, index of correlation is got over
Carry out the value closer to normal mouse.Comparison simultaneously is it is found that the relatively oral finish of emulsion for injection imitates the protective effect of bone marrow suppression
Fruit is more superior.Show: fullerene emulsion for injection has the inhibition of mouse bone marrow cells caused by chemotherapeutics CTX more obvious
Protecting effect.
8 white blood cell count(WBC) of table, red blood cell count(RBC), platelet count, hemoglobinometry data
Test example six: the Hepetoma of endohedral fullerene emulsion for injection
Having investigated fullerene content is 1mg/ml fullerene emulsion for injection (preparing according to 7 method of embodiment) to rat liver cancer
The growth inhibition effect of tumour, specific as follows:
Animal strains: Balb/c female mice, 5 weeks, weight was between 16-20g；
Tumor model: rat liver cancer H22 tumor strain；
Experimental group: being randomly divided into medicine group A, medicine group B and control group C, and every group 6.
Administration mode: (1) applying 1mg/ml fullerene emulsion for injection, intravenous injection to the mouse of medicine group A, and dosage is
200ul/d, successive administration 10 times；(2) 1.2mg/ml fullerene oil group (patent WO2013/ is applied to the mouse of medicine group B
025180 A1), it takes orally, 200ml/kg/d, successive administration 10 times；(3) control group C: physiological saline (Saline)；
It is oral；Dosage:
Experimental method: the H22 liver cancer cells that 100 μ L concentration are 5 × 107/ml are inoculated；Inoculation 24 hours after start to
Medicine, successive administration 10 times；Mouse weight is every other day weighed during experiment and observes tumour growth situation, and observation is to after being inoculated with 15
It terminates experiment, takes mouse tumor to weigh and measure volume, calculates tumour inhibiting rate.
Following result is calculated by above-mentioned anti-cancer methods and tumour inhibiting rate in table 9:
| Case | Average knurl weight (g) | Tumour inhibiting rate |
| A | 0.37±0.02 | 76.5% |
| B | 0.78±0.03 | 45.6% |
| C | 1.3±0.08 | -- |
Fullerene emulsion for injection of the invention inhibits the efficiency of tumour better than fullerene oil it can be seen from the comparison of upper table 9
Product.
Test example seven: the improvement effect of fullerene emulsion for injection to parkinson symptom
Wistar rat, weight 180-200g.5 groups of experiment point, half male and half female, control group not modeling, remaining each group modeling
It is administered after two weeks, successive administration 6 weeks.Fullerene emulsion for injection is divided into high dose group (0.113mg/ml), middle dose group
(0.0565mg/ml), low dose group (0.02820.113mg/ml), dosage 2ml damage model: Ah flutterring using LPS
The behaviouristics and pathological change of parkinson symptom can be simulated after coffee (0.5mg/kg) subcutaneous injection well.After injection 5-15 minutes
The circling behavior to strong side is induced, control rats are Behavioral change.PD group rat rotating cycle with the increase of modeling time and
Increase, the rat rotating cycle of administration group is reduced with the extension of modeling time, and the reduction of high dose group rotating cycle is brighter
It is aobvious.Especially the rat rotating cycle of high dose group and middle metering group is with PD group compared with the time, and rotation number of days has within the 5th, 6 week
Significant difference (P < 0.05) is by data in table 2 it can be concluded that fullerene emulsion for injection has the LPS senile dementia induced
Remarkable result
10 rat circling behavior of table changes (rev/min)
As can be seen from Table 10, fullerene emulsion for injection has clear improvement effect to parkinson symptom compared with control group.
Test example eight: fullerene emulsion for injection anti-aging effects of the present invention
Hydroxyl radical free radical is the important radical form of one kind of harmful to human, the injection being prepared for this patent
Fullerene emulsion has investigated the removal effect of its polyhydroxy free radical.
For using the obtained fullerene emulsion for injection of the method for the present invention (test group), using spin trapping method
(ESR) free radical removal effect is measured.Concrete operations are as follows: react the free radical generated, benefit with ferrous ion for hydrogen peroxide
It is used as spin trapping agent with DMPO (5,5- dimethyl -1- pyrrolin-N- oxide), detection DMPO and hydroxyl radical reaction are raw
At product DMPO-OH signal.
In actual test: the concentration of green vitriol is 0.4mmol/L, and the mass concentration of hydrogen peroxide is 5%, PBS
PH value be 7.4, the concentration of middle C60 is 1mg/ml in emulsion for injection, and the concentration of DMPO is 0.4mol/L, respectively take above five kinds it is molten
50 μ L of liquid is tested after mixing.As can be seen from Figure 4 gained fullerene emulsion for injection has very hydroxyl radical free radical
High elimination efficiency.
In conclusion the invention has the following beneficial effects:
1, fullerene is prepared into injection oil emu for the first time by the present invention, selects suitable oil for injection, the components such as emulsifier
And suitable technological parameter etc., obtained fullerene emulsion bioavilability is high, and stablizes；Polyoxyethylene is avoided for castor-oil plant
Oily sensitization rate is very high, avoids other solvents or cosolvent such as ethyl alcohol and introduces, reduces side effect, safety is higher.
2, inventor has found in this field research and development emulsion for injection, often simultaneously by drug powder, oil for injection, emulsifier
Oily phase is stirred or homogenize, then prepares emulsion again.But fullerene self character cannot be enlightened according to the prior art, it will
Homogeneous mixing all cannot get uniform and stable lotion in any case for fullerene powder, oil for injection and emulsifier, and present always
Suspension.Fullerene powder is such as made to the lotion being prepared again with emulsifier homogeneous after fullerene oil in advance to be overcome
Drawbacks described above, stability is good, remains uniformly not stratified.
3, emulsion prepared by the present invention selects that emulsifying capacity is strong, heat resistance is good, the especially poly- second two of 15- hydroxy stearic acid
Alcohol ester can tolerate 120 DEG C of high temperature and never degenerate, and final emulsion is able to bear 121 DEG C of steam sterilizings.The present invention select relative to it is low at
This emulsifier reduces production cost, is conducive to industrialization production.
4, in injection fullerene emulsion of the invention do not include any solvent and/or cosolvent, as ethyl alcohol, methanol,
Acetone, chloroform isopolarity or nonpolar solvent.
5, the present invention prepares emulsion for injection, is directly entered blood using injection system, avoids first pass effect of hepar, Neng Gou
Reach drug effect under lower fullerene concentration, improves drug availability.
6, the present invention can prepare emulsion using high-temp steam sterilizing mode, avoid that use process is cumbersome, cost is high
Aseptic processing, it is easy to operate, it is capable of the sterilizing production of rapid, high volume, improves production capacity, be conducive to industrialization production.
7, the present invention can solve asking for the small emulsion droplet aggregation of partial size in order to which smaller partial size emulsion is made using microjet
Topic, microjet are in more stable state by emulsion droplet.
8, emulsion for injection of the present invention is superior to the protecting effect of bone marrow suppression compared with oral finish.
9, emulsion for injection of the invention is high to liver cancer inhibiting rate.
10, emulsion for injection of the invention can significantly improve parkinson symptom
11, emulsion for injection of the invention is high to the elimination efficiency of hydroxyl radical free radical.
Detailed description of the invention
Fig. 1 is the partial size DLS data of according to embodiments of the present invention 6 injection fullerene emulsion.
Fig. 2 is the partial size DLS data of according to embodiments of the present invention 7 injection fullerene emulsion.
Fig. 3 is the partial size DLS data of according to embodiments of the present invention 8 injection fullerene emulsion.
Fig. 4 is the removing free radical effect picture of the emulsion for injection of embodiment according to the present invention 7
Specific embodiment
Specific embodiments of the present invention will be described in detail below, it is to be understood that protection scope of the present invention is not
It is restricted by specific implementation.
Unless otherwise explicitly stated, otherwise in entire disclosure and claims, term " includes " or its change
Changing such as "comprising" or " including " etc. will be understood to comprise stated element or component, and not exclude other members
Part or other component parts.
Embodiment 1 fullerene oil
Fullerene powder C70 is subjected to ball milling and refines 0.05-1 μm, then by the fullerene powder 3g and olive oil after refinement
100g is mixed, and is placed in ball mill 500 revs/min, ball milling 80h, obtains fullerene oil suspension, then fullerene oil is mixed
Suspension is heated to 40 DEG C, and nitrogen protection, after stirring 12h, centrifugation, filtering obtain fullerene oil solution.
Embodiment 2 fullerene oil
Fullerene powder C60 is subjected to ball milling and refines 0.05-1 μm, then by the fullerene powder 5g and soybean oil after refinement
100g is mixed, and is placed in ball mill 700 revs/min, ball milling 12h, obtains fullerene oil suspension, then fullerene oil is mixed
Suspension is heated to 50 DEG C, and nitrogen protection, after stirring for 24 hours, centrifugation, filtering obtain fullerene oil solution.
Embodiment 3 fullerene oil
Fullerene powder C76 is subjected to ball milling and refines 0.05-1 μm, then by after refinement fullerene powder 1.5 and green bur
Oily 100g is mixed, and is placed in ball mill 1000 revs/min, ball milling 20h, obtains fullerene oil suspension, then by fullerene
Oil suspension is heated to 60 DEG C, and nitrogen protection, after stirring 36h, centrifugation, filtering obtain fullerene oil solution.
Embodiment 4 fullerene oil
Fullerene powder Gd@C82 is subjected to ball milling and refines 0.05-1 μm, then by the fullerene powder 0.7g and tea after refinement
Oily 100g is mixed, and is placed in ball mill 500-1000 revs/min, ball milling 8-20h, obtains fullerene oil suspension, then will
Fullerene oil suspension is heated to 40-60 DEG C, and nitrogen protection, after stirring 12-72h, centrifugation, filtering obtain fullerene oil solution.
Embodiment 5 fullerene oil
Fullerene powder C60 is subjected to ball milling and refines 0.05-1 μm, then by the fullerene powder 3g and olive oil after refinement
100g is mixed, and is placed in ball mill 500 revs/min, ball milling 80h, obtains fullerene oil suspension, then fullerene oil is mixed
Suspension is heated to 40 DEG C, and nitrogen protection, after stirring 12h, centrifugation, filtering obtain fullerene oil solution.
Embodiment 6:
Weigh 200g Fullerene C20 oil, by 30g poloxamer-188,20g 15-hydroxy polyethylene glycol stearate, in advance
To 60 DEG C 0.4g tocopherol is added, dispersion machine 7000rmp, 5min stir evenly to obtain oily phase in heat；Take sodium citrate 3g, glucose
20g, 600g water for injection are preheated to 60 DEG C, and dispersion machine 5000rmp, 5min stir evenly to obtain water phase, will be oily mutually slow at 60 DEG C
Slowly it is added to dispersion machine 9000rmp, 10min dispersion and emulsion in water phase and obtains slightly cream, be cooled to room temperature, put into naturally to thick newborn temperature
Into high pressure homogenizer, 50Mpa homogeneous 5 times, pH to 7.3-7.4, water for injection supplies 1000ml, packing, nitrogen charging, 121 DEG C
Sterilizing 30min obtains fullerene emulsion.Injection fullerene emulsion is diluted with water 100 times, then uses dynamic scattering analysis
Instrument detects its partial size, as shown in Figure 1, fullerene emulsion partial size substantially remains in 50nm.
Embodiment 7:
Weigh 400g fullerene C70 oil, by 60g poloxamer-188,30g 15-hydroxy polyethylene glycol stearate, in advance
To 60 DEG C 0.7g tocopherol is added, dispersion machine 7000rmp, 5min stir evenly to obtain oily phase in heat；Take sodium citrate 6g, glucose
40g, 600g water for injection are preheated to 60 DEG C, and dispersion machine 5000rmp, 5min stir evenly to obtain water phase, will be oily mutually slow at 60 DEG C
Slowly it is added to dispersion machine 9000rmp, 10min dispersion and emulsion in water phase and obtains slightly cream, be cooled to room temperature, put into naturally to thick newborn temperature
Into high pressure homogenizer, 50Mpa homogeneous 5 times, pH to 7.3-7.4 is adjusted, water for injection supplies 1200ml, packing, nitrogen charging, 121
DEG C sterilizing 30min obtain fullerene emulsion.Injection fullerene emulsion is diluted with water 100 times, then with dynamic light scattering point
Analyzer detects its partial size, as shown in Fig. 2, fullerene emulsion partial size substantially remains in 100nm.
Embodiment 8:
Weigh 500g fullerene C76 oil, by 80g poloxamer-188,50g 15-hydroxy polyethylene glycol stearate, in advance
To 60 DEG C 1g tocopherol is added, dispersion machine 7000rmp, 5min stir evenly to obtain oily phase in heat；Take sodium citrate 8g, glucose
50g, 300g water for injection are preheated to 60 DEG C, and dispersion machine 5000rmp, 5min stir evenly to obtain water phase, will be oily mutually slow at 60 DEG C
Slowly it is added to dispersion machine 9000rmp, 10min dispersion and emulsion in water phase and obtains slightly cream, be cooled to room temperature, put into naturally to thick newborn temperature
Into high pressure homogenizer, 50Mpa homogeneous 5 times, pH to 7.3-7.4 is adjusted, water for injection supplies 1000ml, packing, nitrogen charging, 121
DEG C sterilizing 30min obtain fullerene emulsion.Injection fullerene emulsion is diluted with water 100 times, then with dynamic light scattering point
Analyzer detects its partial size, as shown in figure 3, fullerene emulsion partial size substantially remains in 150nm.
Embodiment 9:
Weigh 500g fullerene Gd@C82 oil, by 75g poloxamer-188,60g 15-hydroxy polyethylene glycol stearate,
60 DEG C are preheated to, 1g tocopherol is added, dispersion machine 7000rmp, 5min stir evenly to obtain oily phase；Take sodium citrate 7g, glucose
60g, 200g water for injection are preheated to 60 DEG C, and dispersion machine 5000rmp, 5min stir evenly to obtain water phase, will be oily mutually slow at 60 DEG C
Slowly it is added to dispersion machine 9000rmp, 10min dispersion and emulsion in water phase and obtains slightly cream, be cooled to room temperature, put into naturally to thick newborn temperature
Into high pressure homogenizer, 50Mpa homogeneous 5 times, pH to 7.3-7.4 is adjusted, water for injection supplies 1000ml, packing, nitrogen charging, 121
DEG C sterilizing 30min obtain fullerene emulsion.
Embodiment 10:
Weigh 1000g Fullerene C20 oil, by 160g poloxamer-188,100g 15-hydroxy polyethylene glycol stearate,
65 DEG C are preheated to, 2g tocopherol is added, dispersion machine 6000rmp, 5min stir evenly to obtain oily phase；Take sodium citrate 150g, grape
Sugared 100g, 3500g water for injection is preheated to 65 DEG C, and dispersion machine 5000rmp, 5min stir evenly to obtain water phase, will be oily at 56 DEG C
It is mutually slowly added into dispersion machine 9000rmp, 10min dispersion and emulsion in water phase and obtains slightly cream, be cooled to room temperature naturally to thick newborn temperature,
Put into high pressure homogenizer, 50Mpa homogeneous 5 times, adjust pH to 7.3-7.4, water for injection supplies 5000ml, packing, nitrogen charging,
121 DEG C of sterilizing 30min obtain fullerene emulsion.
Embodiment 11:
Weigh 300g fullerene C70 oil, by 45g poloxamer-188,33g 15-hydroxy polyethylene glycol stearate, in advance
To 70 DEG C 0.4g tocopherol is added, dispersion machine 8000rmp, 5min stir evenly to obtain oily phase in heat；Take sodium citrate 4.5g, grape
Sugared 35g, 100g water for injection is preheated to 70 DEG C, and dispersion machine 5000rmp, 5min stir evenly to obtain water phase, by oily phase at 70 DEG C
It is slowly added into dispersion machine 9000rmp, 10min dispersion and emulsion in water phase and obtains slightly cream, be cooled to room temperature, throw naturally to thick newborn temperature
Enter into high pressure homogenizer, 50Mpa homogeneous 5 times, adjust pH to 7.3-7.4, water for injection supplies 450ml, packing, nitrogen charging, 121
DEG C sterilizing 30min obtain fullerene emulsion.
Embodiment 12:
Weigh 600g fullerene C76 oil, by 80g poloxamer-188,60g 15-hydroxy polyethylene glycol stearate, in advance
To 60 DEG C 1.3g tocopherol is added, dispersion machine 6000rmp, 5min stir evenly to obtain oily phase in heat；Take sodium citrate 9g, glucose
60g, 400g water for injection are preheated to 60 DEG C, and dispersion machine 6000rmp, 7min stir evenly to obtain water phase, will be oily mutually slow at 60 DEG C
Slowly it is added to dispersion machine 01000rmp, 15min dispersion and emulsion in water phase and obtains slightly cream, be cooled to room temperature, throw naturally to thick newborn temperature
Enter into high pressure homogenizer, 50Mpa homogeneous 5 times, adjust pH to 7.3-7.4, water for injection supplies 1200ml, packing, nitrogen charging,
121 DEG C of sterilizing 30min obtain fullerene emulsion.
Embodiment 13:
Weigh 200g fullerene Gd@C82 oil, by 30g poloxamer-188,20g 15-hydroxy polyethylene glycol stearate,
60 DEG C are preheated to, 0.4g tocopherol is added, dispersion machine 7000rmp, 5min stir evenly to obtain oily phase；Take sodium citrate 3g, grape
Sugared 20g, 50g water for injection is preheated to 60 DEG C, and dispersion machine 5000rmp, 5min stir evenly to obtain water phase, by oily phase at 60 DEG C
It is slowly added into dispersion machine 9000rmp, 10min dispersion and emulsion in water phase and obtains slightly cream, be cooled to room temperature, throw naturally to thick newborn temperature
Enter into high pressure homogenizer, 50Mpa homogeneous 5 times, adjust pH to 7.3-7.4, water for injection supplies 400ml, packing, nitrogen charging, 121
DEG C sterilizing 30min obtain fullerene emulsion.
Embodiment 14:
It weighs 200g Fullerene C20 oil, gather 20g soybean lecithin, 15g egg yolk lecithin, 20g15- hydroxy stearic acid
Glycol ester is preheated to 65 DEG C, 0.4g tocopherol is added, dispersion machine 8000rmp, 7min stir evenly to obtain oily phase；Take citric acid
Sodium 3g, glucose 20g, 50g water for injection, are preheated to 65 DEG C, and dispersion machine 6000rmp, 6min stir evenly to obtain water phase, at 65 DEG C
It is lower oil is mutually slowly added into dispersion machine 9000rmp, 10min dispersion and emulsion in water phase to obtain slightly newborn, it is down to naturally to thick cream temperature
It after room temperature, puts into high pressure homogenizer, 50Mpa homogeneous 6 times, adjusts pH to 7.3-7.4, water for injection supplies 400ml, goes out
Bacterium, packing.
Embodiment 15:
Weigh 100g Fullerene C20 oil, by 10g soybean lecithin, 10g phosphatidyl choline, 5g polyoxyethylene groups castor oil,
Poloxamer -407 15g are preheated to 60 DEG C, 0.2g tocopherol are added, dispersion machine 7000rmp, 5min stir evenly to obtain oily phase；It takes
Sodium citrate 2g, glucose 10g, 50g water for injection, are preheated to 60 DEG C, and dispersion machine 7000rmp, 5min stir evenly to obtain water phase,
Oil is mutually slowly added into dispersion machine 9000rmp, 10min dispersion and emulsion in water phase at 60 DEG C and obtains slightly cream, certainly to thick newborn temperature
It is so cooled to room temperature, puts into high pressure homogenizer, 50Mpa homogeneous 5 times, with pH to 7.3-7.4 is adjusted, water for injection is supplied
200ml, sterilizing, packing.
Embodiment 16:
It weighs 200g Fullerene C20 oil, gather 15g PLURONICS F87,15g egg yolk lecithin, 10g15- hydroxy stearic acid
Glycol ester is preheated to 60 DEG C, 0.3g tocopherol is added, dispersion machine 7000rmp, 5min stir evenly to obtain oily phase；Take citric acid
Sodium 3g, glucose 25g, 50g water for injection, are preheated to 60 DEG C, and dispersion machine 6000rmp, 6min stir evenly to obtain water phase, at 60 DEG C
It is lower oil is mutually slowly added into dispersion machine 9000rmp, 10min dispersion and emulsion in water phase to obtain slightly newborn, it is down to naturally to thick cream temperature
It after room temperature, puts into high pressure homogenizer, 50Mpa homogeneous 4 times, adjusts pH to 7.3-7.4, water for injection supplies 400ml, goes out
Bacterium, packing.
Embodiment 17:
Weigh 200g Fullerene C20 oil, by 25g ethyl oleate, 15g PLURONICS F87, the poly- second of 20g15- hydroxy stearic acid
Diol ester is preheated to 70 DEG C, 0.4g tocopherol is added, dispersion machine 6000rmp, 7min stir evenly to obtain oily phase；Take sodium citrate
3g, glucose 20g, 50g water for injection, are preheated to 60 DEG C, and dispersion machine 6000rmp, 6min stir evenly to obtain water phase, at 60 DEG C
Oil is mutually slowly added into dispersion machine 9000rmp, 10min dispersion and emulsion in water phase and obtains slightly cream, is down to room naturally to thick newborn temperature
Wen Hou is put into high pressure homogenizer, 50Mpa homogeneous 5 times, adjusts pH to 7.3-7.4, and water for injection supplies 400ml, sterilize,
Packing.
Embodiment 18:
Weigh 200g Fullerene C20 oil, by 10g Labraso, 20g PLURONICS F87,10g15-
Hydroxy stearic acid macrogol ester is preheated to 60 DEG C, 0.4g tocopherol is added, dispersion machine 6000rmp, 7min stir evenly oily
Phase；Sodium citrate 3g, glucose 20g, 50g water for injection are taken, is preheated to 60 DEG C, dispersion machine 6000rmp, 6min are stirred evenly
Oil is mutually slowly added into dispersion machine 9000rmp, 10min dispersion and emulsion in water phase at 60 DEG C and obtains slightly cream by water phase, to thick cream temperature
Degree nature is cooled to room temperature, and is put into high pressure homogenizer, 50Mpa homogeneous 5 times, and pH to 7.3-7.4 is adjusted, and water for injection is supplied
400ml, sterilizing, packing.
Embodiment 19:
Weigh 200g Fullerene C20 oil, by 30g poloxamer-188,20g 15-hydroxy polyethylene glycol stearate, in advance
To 60 DEG C 0.4g tocopherol is added, dispersion machine 7000rmp, 5min stir evenly to obtain oily phase in heat；Take sodium citrate 3g, glucose
20g, 600g water for injection are preheated to 60 DEG C, and dispersion machine 5000rmp, 5min stir evenly to obtain water phase, will be oily mutually slow at 60 DEG C
Slowly it is added to dispersion machine 9000rmp, 10min dispersion and emulsion in water phase and obtains slightly cream, be cooled to room temperature naturally to thick newborn temperature, it is micro- to penetrate
Flowing homogeneous to emulsion droplet size is 50-100nm, pH to 7.3-7.4, and water for injection supplies 1000ml, packing, nitrogen charging, 121 DEG C go out
Bacterium 30min obtains fullerene emulsion.
Embodiment 20:
Weigh 400g fullerene C70 oil, by 60g poloxamer-188,30g 15-hydroxy polyethylene glycol stearate, in advance
To 60 DEG C 0.7g tocopherol is added, dispersion machine 7000rmp, 5min stir evenly to obtain oily phase in heat；Take sodium citrate 6g, glucose
40g, 600g water for injection are preheated to 60 DEG C, and dispersion machine 5000rmp, 5min stir evenly to obtain water phase, will be oily mutually slow at 60 DEG C
Slowly it is added to dispersion machine 9000rmp, 10min dispersion and emulsion in water phase and obtains slightly cream, be cooled to room temperature naturally to thick newborn temperature, it is micro- to penetrate
Flowing homogeneous to emulsion droplet size is 50-100nm, adjusts pH to 7.3-7.4, and water for injection supplies 1200ml, packing, nitrogen charging, 121 DEG C
Sterilizing 30min obtains fullerene emulsion.
The aforementioned description to specific exemplary embodiment of the 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 explaining specific principle of the invention and its actually answering
With so that those skilled in the art can be realized and utilize a variety of different exemplary implementation schemes of the invention 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 injection fullerene emulsion includes weight percent fullerene oil 15-50%, emulsifier 4-17%, stabilizer
0.3-1%, excipient 2-9% and surplus water for injection, and do not include solvent or cosolvent, the fullerene emulsion is pH7.3-
7.4 stable oil-in-water emulsions.
2. fullerene emulsion as described in claim 1, which is characterized in that the partial size 50-150nm of the emulsion droplet.
3. fullerene emulsion as described in claim 1, which is characterized in that the fullerene oil is that fullerene is dissolved into injection
With in oil, the solubility is 1-10mg/ml.
4. fullerene emulsion as described in claim 1, which is characterized in that the fullerene is empty fullerene and/or gold
Belong to fullerene, including fullerene C2n、M@C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2nAnd MxA3-xN@
C2nAny one of, wherein M and A is metallic element, and the M and A are selected from any one in Sc, Y and lanthanide element
Kind；30≤n≤60.
5. fullerene emulsion as claimed in claim 3, which is characterized in that the oil for injection is olive oil, soybean oil, blueness
Bur oil, linseed oil, sunflower oil, SIMMONDSIA CHINENSIS SEED OIL, peanut oil, tea oil, tea oil, rose hip oil, macadamia nut oil, avocado oil,
At least one of castor oil, maize germ and corn oil.
6. fullerene emulsion as described in claim 1, which is characterized in that the emulsifier is caprylic capric polyethylene glycol glycerol
Ester, ethyl oleate, soybean lecithin, egg yolk lecithin, phosphatidyl choline, poloxamer-188,15- hydroxy stearate acid polyethylene glycol
It is one or more of in ester.
7. fullerene emulsion as claimed in claim 6, which is characterized in that the emulsifier is poloxamer-188 and 15- hydroxyl
The weight ratio of base stearic acid macrogol ester is (0.6-4): 1 mixture.
8. a kind of preparation method of injection fullerene emulsion as described in claim 1, which is characterized in that including following steps
It is rapid:
Step (1) prepares fullerene oil: after fullerene end and oil for injection are sufficiently mixed uniformly, it is placed in ball mill, ultrasound,
Stirring, heating, dissolve fullerene sufficiently in oil for injection, and fullerene oil is obtained by filtration；
Step (2) prepares oily phase: emulsifier, fullerene oil being preheated, addition oiliness excipient, which is placed in dispersion machine machine, to be stirred
It is uniform to obtain oily phase；
Step (3) prepares water phase: by stabilizer, aqueous vehicle, water for injection, preheating, which is placed in dispersion machine, stirs evenly to obtain water
Phase；
Step (4) prepares emulsion: oil being mutually slowly added into water phase to be placed in dispersion machine is dispersed with stirring uniform, microjet or height
Press homogeneous to get oil-in-water type fullerene emulsion.
9. fullerene emulsion as described in claim 1, which comprises the steps of:
Step (1) prepares fullerene oil: fullerene powder being carried out ball milling and refines 0.05-1 μm, then by the fullerene powder after refinement
End carries out mixing and ball milling 8-20h with oil for injection, obtains fullerene oil suspension, then fullerene oil suspension is heated to 40-
60 DEG C, nitrogen protection, after stirring 24-72h, centrifugation, filtering obtain fullerene oil solution；
Step (2) prepares oily phase: emulsifier, fullerene oil are preheated 55-70 DEG C, be added oiliness excipient be placed in dispersion machine with
The revolving speed stirring 2-10min of 5000-10000rmp is uniformly dispersed to get oily phase；
Step (3) prepares water phase: by stabilizer, aqueous vehicle, water for injection, preheat 55-70 DEG C, be placed in dispersion machine with
The revolving speed stirring 2-10min dispersion of 5000-10000rmp stirs evenly, and obtains water phase；
Step (4) prepares emulsion: being mutually slowly distributed in water phase at 60-80 DEG C by oily, is stirred with the revolving speed of 7000-10000rmp
It mixes 5-15min and thick cream is made；Thick cream temperature is cooled to room temperature, and is put into microjet or high pressure homogenizer, in pressure 50-
Under 60Mpa, homogeneous 5-6 times is 140-150nm or emulsion partial size 50-100nm is made to get essence in microjet until emulsion partial size
Cream adjusts pH to 7.3-7.4, and water for injection is supplied, packing, nitrogen charging, sterilizing.
10. a kind of injection fullerene emulsion as described in claim 1 treats tumour, Parkinson's disease, bone marrow suppression in preparation
The effect in application or removing interior free yl antiaging agent in agent drug.
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| PCT/CN2018/105240 WO2019052471A1 (en) | 2017-09-12 | 2018-09-12 | Fullerene composition and preparation method and use thereof |
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| CN110051626A (en) * | 2018-01-18 | 2019-07-26 | 杜权 | A kind of two-phase oil formulation and its application |
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