CN109481463B - Oral fullerene emulsion, preparation method and application - Google Patents
Oral fullerene emulsion, preparation method and application Download PDFInfo
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Abstract
The invention discloses an oral fullerene emulsion, a preparation method and an application thereof, wherein the oral fullerene emulsion comprises the following components in percentage by weight: 10-50% of fullerene oil, 4-30% of emulsifier, 0.1-0.2% of auxiliary emulsifier and deionized water for supplement, and the emulsion is safe and stable and has high bioavailability.
Description
Technical Field
The invention relates to the field of medicines, in particular to an oral fullerene emulsion and a preparation method thereof.
Background
C60 fullerene was discovered by scientists Kroto, Smalley, Curl, et al in 1985 when studying carbon elements deep in space, and three people gained a Nobel prize for chemistry in 1996. Fullerene is an allotrope of carbon, as well as diamond and graphite. C60 is a spherical molecule consisting of 60 carbon atoms, consisting of 12 pentagons and 20 hexagons, each carbon atom and the three adjacent carbon atoms passing through the SP2Hybridized to form bonds, known as "soccer limonene" because it resembles a soccer ball.
The series of molecules having a cage-like carbon atom cluster structure is collectively referred to as fullerenes, which is another allotrope of carbon elements other than graphite, diamond, and amorphous carbon. The fullerene mainly comprises hollow fullerene, embedded fullerene, fullerene derivatives, heterocyclic fullerene and the like. Common species are C60, C70, C76, C84 and the like.
The fullerene has strong electron accepting capacity due to a large pi bond conjugated system formed by a plurality of P orbitals, has excellent free radical scavenging performance due to unique structure and physicochemical properties, is called as free radical sponge, and simultaneously shows excellent oxidation resistance. So that it has attracted much attention in the fields of cosmetic materials, biomedicines, and the like.
By embedding C60 in the surfactant, C60 can eliminate reactive oxygen species in the cell, inhibit mitochondrial depolarization, activation of cysteine protease, exposure of phosphatidylserine on the cell membrane, and DNA division, and C60 exhibits the effect of protecting cells from oxidative apoptosis. The C60 liposome complex has antioxidant effect by preventing UVA from damaging skin structure, cell nucleus and collagen fiber and permeating into human skin tissue, is 172 times of vitamin C, and has affinity with free radical.
Professor Fathi Moussa engaged in the research work of C60 nature for a long time, and as the first person to dissolve fullerene in olive oil, they were fed to rats once every two weeks for 10-17 months (4 mg fullerene per kg body weight), control rats died for 17-38 months, and the test group was extended to 59-66 months, and found that fullerene had a long life and health-promoting effect. No abnormality exists in physiological performance regardless of body weight, and C60 is not found to be toxic or biogenetic, but C60 in a certain amount has the performance of scavenging free radicals, so that animals are protected from harm caused by excessive free radicals.
In the prior art, fullerene C is60The studies conducted in olive oil revealed that it scavenges free radicals and prolongs the life of test rats without affecting physiological performance, but fullerene C dissolved in olive oil60After entering the animal body, the digestion and absorption conditions are not ideal, and meanwhile, after a large amount of grease is absorbed into the body, the grease can be applied to intestinal flora in the body, and patients with high blood fat, high blood sugar and high blood sugar can aggravate the disease condition because of excessive grease absorption. Therefore, the direct administration of oil will affect the efficacy of the drug. Patent WO2013/025180a1 discloses a method for preparing fullerene vegetable oil by mixing fullerene powder with vegetable oil, ball milling, centrifuging, filtering to obtain fullerene vegetable oil, and administering the fullerene vegetable oil in pure form or in the form of an emulsion in water. When the pure form administration is adopted, the fullerene vegetable oil is directly drunk to treat diseases, a large amount of vegetable oil is needed to be taken to achieve the curative effect, the patients with the three highs are used, and the compliance of the patients is lower. Administration in the form of water includes various oral forms. The emulsion is two mutually insoluble liquids, is prepared into a stable oil-in-water emulsion preparation for oral administration, has good dispersion effect and large effective surface area, and is beneficial to the release, dissolution and absorption of the medicament; the emulsion contains emulsifier, has surface activity, and can improve gastrointestinal mucosa performance and promote drug absorption; after being absorbed, the grease in the emulsion can promote bile secretion, increase the flow rate of blood and lymph fluid and be beneficial to the dissolution and absorption of medicaments; the oil in the emulsion is digested to generate linoleic acid and oleic acid, which can inhibit gastrointestinal peristalsis and prolong the retention time of the medicine in small intestine; the oleaginous substances in the emulsion may also be transported and absorbed through the lymphatic system.
In order to improve the bioavailability and safety of the fullerene, the oral fullerene emulsion selected by the invention has not been studied.
Disclosure of Invention
In order to overcome the technical problems, the invention provides the fullerene emulsion for oral administration, which is prepared by dissolving fullerene in vegetable oil, uniformly dispersing an emulsifier, fullerene oil and deionized water by using a high-pressure homogenizer or microjet to form an emulsion, and can accelerate the absorption and drug effect of the fullerene and improve the bioavailability after being used in an oral administration mode, thereby achieving the effects of removing free radicals in a human body, relieving body injury, resisting aging and the like without any side effect.
Another object of the present invention is a method for preparing an oral fullerene emulsion that has improved solubility.
The invention is realized by the following technical scheme:
the invention discloses an oral fullerene emulsion which is characterized by comprising the following components in percentage by weight: 10-50% of fullerene oil, 4-30% of emulsifier, 0.1-0.2% of auxiliary emulsifier and deionized water.
Further preferably, the oral fullerene emulsion is characterized by comprising the following components in percentage by weight: 18-40% of fullerene oil, 8-20% of emulsifier, 0.1-0.2% of auxiliary emulsifier and deionized water.
The oral fullerene emulsion is an oil-in-water fullerene emulsion, and the particle size of emulsion droplets is 50-200 nm. More preferably 50-150 nm.
The fullerene oil consists of (by weight parts) fullerene and vegetable oil (0.1-10) and (10-40). More preferably, the fullerene oil consists of fullerene and vegetable oil (1-5) to (15-25) in parts by weight. The best fullerene oil is composed of fullerene and vegetable oil in a weight ratio of 1: 20.
Preferably, in the above technical solution, the fullerene is a hollow fullerene and/or a metal fullerene. Including but not limited to fullerene C2n、M@C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2nAnd MxA3-xN@C2nAny one of (1), wherein M and A are both metal elements, and both M and A are selected from any one of Sc, Y and lanthanide metal elements; n is more than or equal to 30 and less than or equal to 60; x is more than or equal to 0 and less than or equal to 3.
More preferably, the fullerene is selected from the group consisting of C60、C70、C76、C82、C84One or more than one of the components.
The vegetable oil includes, but is not limited to, at least one of olive oil, soybean oil, prinsepia seed oil, linseed oil, sunflower seed oil, jojoba oil, peanut oil, tea tree oil, rose hip oil, nut oil, avocado oil, castor oil, corn germ oil, and corn oil. More preferably soybean oil, olive oil, castor oil, and tea oil. More preferably soybean oil, which has high fullerene solubility and contains a large amount of unsaturated fatty acids.
The emulsifier of the invention selects auxiliary materials with strong emulsifying capacity, high temperature resistance and easy storage according to the fullerene. Preferred emulsifiers include, but are not limited to, one or more of polyoxyethylene castor oil, polyglycerol oleate, oleoyl polyoxyethylene glyceride, caprylic capric macrogol glyceride, polyethylene glycol-15-hydroxystearate, polyoxyethylene laurate, tween 80, soya lecithin, egg yolk lecithin, hydrogenated soya lecithin. Preferably, the emulsifier is selected from soybean phospholipid and polyoxyethylene castor oil. The two emulsifiers are compounded to have better stability and enhanced emulsifying capacity.
On the basis of measuring the drug-adjuvant compatibility, aiming at the in-vivo absorption characteristic of the oral preparation, the oil phase and the emulsifier with the best fullerene solubility are selected for compatibility, so that the maximum content of the drugs in the oral emulsion is ensured.
The inventor finds that the effect of the single emulsifier is not obvious in a large amount of screening processes, and when the co-emulsifier is selected and used together with the emulsifier, the cost can be reduced, the emulsifying capacity is high, the toxicity is low, and more importantly, the stability is increased. The auxiliary emulsifier comprises ethyl oleate, propylene glycol, glycerol, ethanol, sodium citrate, sodium carboxymethylcellulose, sodium dodecyl benzene sulfonate, sodium alginate, povidone, stearic acid, polyethylene glycol 400, polyethylene glycol 600 and xanthan gum. The preferable coemulsifier is sodium citrate which is safe, nontoxic, good in fluidity and capable of being degraded and excreted quickly after entering a human body.
Further preferably, the ratio of soybean phospholipids: polyoxyethylene castor oil: when the sodium citrate is (4-5): (4.5-5): (0.2-0.3), a stable fullerene emulsion can be prepared.
The fullerene emulsion water-soluble auxiliary material comprises essence, preservative and the like.
The fullerene emulsion can be used as one of raw materials of other pharmaceutical compositions, and the dosage of the fullerene emulsion is 0.1-99.9%.
The fullerene emulsion can be prepared into pharmaceutically acceptable dosage forms with pharmaceutically acceptable carriers. The dosage form is an oral administration route, and comprises one of capsules, tablets, dripping pills, granules, concentrated pills, oral liquid and mixtures.
For the fullerene emulsion of the present invention, the preparation for oral administration may contain conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents, and the tablet may be coated if necessary.
Suitable fillers include cellulose, mannitol, lactose and other similar fillers. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives (e.g. sodium starch glycolate). Suitable lubricants are, for example, magnesium stearate and the like. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate and the like.
The fullerene emulsions of the present invention can be prepared into solid oral compositions by methods commonly used in the art, such as mixing, filling, tableting, and the like, and repeated mixing can result in uniform distribution of the active in the composition as a whole using a large amount of filler.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; solutions are generally prepared by dissolving the active substance in a carrier and filter sterilizing and then sealing it before filling it in a suitable vial or ampoule. Adjuvants such as local anesthetics, preservatives and buffering agents can also be dissolved in the vehicle. To improve the stability of the liquid unit dosage form, the composition can be frozen after filling into vials and the water removed under vacuum.
In preparing the fullerene emulsion of the present invention into a medicament, one or more suitable pharmaceutically acceptable carriers selected from the group consisting of: sugar alcohols such as mannitol, sorbitol, xylitol; amino acids, such as cysteine hydrochloride, methionine, glycine; inorganic salts such as carbonates of monovalent alkali metals, phosphates or aqueous solutions thereof, sodium chloride, potassium chloride, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, calcium carbonate, calcium hydrogen carbonate; inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid; organic acids such as acetic acid, vitamin C, thioglycolic acid; organic acid salts such as acetate, alginate, sodium lactate, disodium EDTA, calcium sodium EDTA, stearates such as calcium stearate, magnesium stearate; oligosaccharides, polysaccharides, cellulose and its derivatives, such as maltose, glucose, fructose, dextran, sucrose, lactose, cyclodextrins (e.g. beta-cyclodextrin), starch; a silicon derivative; gelatin; polyvinylpyrrolidone; glycerol; agar; surfactants (e.g., tween 80); polyethylene glycol; a phospholipid material; kaolin; talc powder, and the like.
The invention also discloses a preparation method of the fullerene emulsion for injection, which comprises the following steps:
(1) preparing fullerene oil:
(2) preparing an oil phase:
(3) preparing an aqueous phase:
(4) preparing an oil-in-water fullerene emulsion:
and (2) fully and uniformly mixing the fullerene powder and the vegetable oil in the step (1), placing the mixture in a ball mill, performing ultrasonic treatment, stirring and heating to fully dissolve the fullerene in the vegetable oil, and filtering to obtain the fullerene oil.
Further preferably, the fullerene powder is ball-milled and refined by 0.05-1 μm in the step (1), then the refined fullerene powder is mixed with vegetable oil, the mixture is placed in a ball mill for 500-1000 r/min and ball-milled for 8-20h to obtain fullerene oil suspension, then the fullerene oil suspension is heated to 0-60 ℃, protected by nitrogen, stirred for 12-72h, centrifuged and filtered to obtain fullerene oil solution.
Further preferably, the fullerene powder is ball-milled and refined by 0.05-1 μm in the step (1), the powder and the vegetable oil are fully mixed uniformly, then the mixture is placed in a ball mill for 700 revolutions per minute at 500-50 ℃ and is ball-milled for 6-10 hours to obtain fullerene oil suspension, then the suspension is heated to 0-50 ℃ under the protection of ultrasound and nitrogen, the suspension is stirred and heated for 10-15 hours to fully dissolve the fullerene in the oil auxiliary materials, and the fullerene oil is obtained through centrifugation and filtration.
And (3) preheating the emulsifier, the co-emulsifier and the fullerene oil in the step (2), and placing the mixture in a dispersion machine to be uniformly stirred to obtain an oil phase.
Further preferably, in the step (2), the emulsifier, the co-emulsifier and the fullerene oil are preheated to 55-70 ℃, and are placed in a dispersion machine to be stirred at the rotating speed of 5000-.
Emulsion aqueous auxiliary materials such as essence, preservative and the like can also be added into the water phase in the step (3).
In the step (3), the water-soluble auxiliary materials and the deionized water are preheated and placed in a dispersion machine to be uniformly stirred to obtain the water phase.
Further preferably, in the step (3), the water-soluble auxiliary material is added into deionized water to be preheated to 50-60 ℃, placed in a dispersion machine 3000-7000rmp and stirred for 8-15min to obtain the water phase.
And (4) slowly adding the oil phase into the water phase, uniformly stirring and dispersing in a dispersion machine, and homogenizing under high pressure to obtain the oil-in-water fullerene emulsion.
Further preferably, in the step (4), the oil phase is slowly added into the water phase at 50-60 ℃ to disperse 7000-.
The preferable homogenizing pressure and homogenizing times of the invention are obtained by screening according to the particle size and stability of the emulsion. The higher the pressure is, the more the homogenization times are, the smaller and more uniform the emulsion particle size is, and the more stable the emulsion is; however, if the number of homogenization is too large and the particle size of the emulsion is too small, the contact area of the emulsion droplets becomes large, resulting in an increase in the aggregation ability of the emulsion droplets and a decrease in the stability of the emulsion. The 140-150nm emulsion obtained by homogenization has good stability and no aggregation phenomenon. The invention adopts the micro-jet technology to prepare the emulsion with smaller particle size, so that the problem of aggregation of emulsion droplets with small particle size can be solved, and the micro-jet enables the emulsion droplets to be in a more stable state.
The invention also provides the application of the oral fullerene emulsion in preparing a medicament for treating tumors, in particular in preparing a medicament for treating bone marrow suppression.
The invention also provides application of the oral fullerene emulsion in preparation of a medicine for treating Parkinson's disease.
The invention also provides the function of the oral fullerene emulsion in clearing free radicals in vivo and resisting aging.
Advantageous effects
In order to better describe the advantageous effects of the present invention, the following test examples are provided to illustrate
Test example I screening of vegetable oils in Fullerene emulsion
The method comprises the following steps: fully and uniformly mixing fullerene powder and the oil auxiliary materials in the table 1, placing the mixture in a ball mill, performing ball milling for 8 hours at 700 r/min, then performing ultrasonic and stirring heating on the mixture at 40 ℃ for 12 hours to fully dissolve fullerene in the oil auxiliary materials, and finally filtering to obtain fullerene oil.
Table 1: drug-adjuvant compatibility screening
As a result: the vegetable oil shown in table 1 can only be used as an oil phase in the emulsion, and the vegetable oil has relatively good solubility to various fullerenes, and is preferably soybean oil, olive oil and tea oil. The fullerene, polyoxyethylene castor oil, polyglycerol oleate, caprylic/capric macrogol glyceride, propylene glycol monocaprylate and the like can be used as oil phase and also can be used as emulsifier, and the solubility of various fullerenes is far less than that of vegetable oil to fullerene. And similarly, the fullerene is mixed with the emulsifier or the coemulsifier, and the fullerene can not be dispersed into the grease of the emulsifier or the coemulsifier. In conclusion, the vegetable oil is the oil phase with the best fullerene solubility, so that the maximum drug content in the oral emulsion can be ensured in the preparation process of the emulsion.
Test example screening test for emulsifier
The method comprises the following steps: fullerene oil 20g, polyoxyethylene castor oil Table 2
Table 2: preparation of Fullerene emulsion screening
Unit: g to 100g
As can be seen from table 2, when the amount of the emulsifier used is small, oil-water separation occurs, and when the proportion of the emulsifier is increased, the emulsifier can form milk, but the stability is not sufficient, and water-milk separation occurs after the formation of milk. Therefore, it is not possible to obtain a stable fullerene emulsion by using the polyoxyethylene castor oil alone as an emulsifier, and another emulsifier is optionally added and used.
(II) method: selection of composite emulsifier
When the inventor selects the auxiliary materials compounded with polyoxyethylene, the inventor finds that when tween-80 is filled, the oil-water separation state still appears when the adding amount reaches 2 percent, the oil-water separation state can not appear when the natural phospholipid emulsifier is used in a small amount, and the natural phospholipid can promote the drug absorption and is widely used for preparing the emulsion. The mixed emulsifier has good emulsifying effect, and the phospholipid emulsifier can improve the bioavailability of the emulsion.
Weighing 20g of fullerene oil and the auxiliary materials in the table 3, adding 6g of deionized water and 74g of deionized water, and observing the state of an emulsion system after 7000rmp10min of a dispersion machine. The following results are shown in tables 3 and 4: the soybean lecithin is the most preferable, and has the advantages of good emulsifying effect, promotion of emulsion absorption, good smell and the like. Experimental items 4 and 6 can obtain stable emulsions, but the use of the emulsifier at the minimum is the preferred choice, so 4 is selected as the preparation method.
Table 3: screening of phospholipid emulsifiers
Table 4: screening the compatibility of mixed emulsifier
Unit: g
Test example three selection of Co-emulsifier
As the formula does not use the auxiliary emulsifier, the dosage of the emulsifier is large, and the cost is high, the auxiliary emulsifier is added on the basis to reduce the dosage of the emulsifier.
The auxiliary emulsifier generally has no emulsifying capacity or very weak emulsifying capacity, plays a role in increasing the stability of the emulsion in the process of preparing the emulsion, can improve the viscosity of the emulsion and increase the strength of an emulsion film so as to increase the stability of the emulsion, and the potential of an emulsion system is between 20 to 40 mv, which is beneficial to the stability of the emulsion, so that the ionic salt type auxiliary emulsifier is selected, namely sodium citrate, sodium alginate, dodecyl sulfonic acid and sodium carboxymethylcellulose.
TABLE 5 coemulsifier Property screening
From table 5, sodium citrate is the preferred choice.
Table 6: adding co-emulsifier agent sodium citrate compatibility screening
Unit: g to 100g
The final stable fullerene emulsion prepared from table 6 was obtained when the soy phospholipid: polyoxyethylene castor oil: sodium citrate ═ 4:4.5:0.2 or soy lecithin: polyoxyethylene castor oil: when the ratio of sodium citrate to sodium citrate is 5.5:4:0.3, stable fullerene emulsion can be prepared.
Selection of Process parameters in test example four
The method comprises the following steps: the recipe and preparation process of example 1 were followed, with the parameters as given in tables 7 to 9.
Table 7: screening of emulsification temperature:
the Ke value is a centrifugal stability parameter, and a smaller Ke value indicates a more stable emulsion. As can be seen from Table 7, the emulsion preparation temperature at 70 ℃ gave the lowest centrifuge stability parameters and the best emulsion stability.
The high-pressure homogenizer plays a role in emulsifying and homogenizing in the process of preparing the emulsion, so that the emulsion prepared under different pressures has different particle sizes, the stability of the final emulsion is influenced, and the particle sizes of the emulsion are detected after homogenizing for 5 times.
TABLE 8 high pressure homogeneous pressure Screen
From Table 8: the pressure of the homogenizer is 60MPa and 50MPa, the grain diameter of the emulsion is not obviously different, and the homogenizing pressure is 50MPa according to the principle of low cost.
Homogenizing under the same pressure of 50Mpa, wherein the homogenizing times influence the particle size of the emulsion, and the more homogenizing times, the smaller and more uniform the particle size of the emulsion and the more stable the emulsion; however, if the number of homogenization is too large and the particle size of the emulsion is too small, the contact area of the emulsion droplets becomes large, resulting in an increase in the aggregation ability of the emulsion droplets and a decrease in the stability of the emulsion.
Table 9: high pressure homogenization frequency screening
From Table 9: the homogenization times have no obvious difference between 4-time particle size and 5-time particle size, and the homogenization times are 4 times as the preparation times according to the low-cost principle.
Experimental example fiveFullerene oral emulsion in vivo level chemoprotective efficacy
Animal model: 4-5 week ICR mice, randomized into 4 groups of 6 mice each, drug A: CTX +1mg/ml oral emulsion group, and the administration is performed by intragastric administration, 100ul each time; drug group B: CTX plus 5mg/ml fullerene oil, and the administration is carried out by intragastric administration, each time 100 ul; control group C: saline (Saline), Cyclophosphamide (CTX) panel D. The mice were inoculated subcutaneously with 106 mouse liver cancer cells (H22 cells), and experiments were carried out 5 to 7 days after inoculation when the tumor diameter reached about 5 mm. The dose of CTX administered was 60mg/kg mouse body weight. The administration was started on day seven after tumor inoculation, as the first day of starting the experiment, once a day for 5 consecutive days, on day four, day seven, day ten, day fourteen and day seventeen, respectively, blood was taken from the orbital of the mouse (20 μ l), and blood routine was examined with an automatic blood cell analyzer, wherein the main indices related to bone marrow suppression were white blood cell count (WBC), red blood cell count (RBC), platelet count (PLT), hemoglobin assay (HGB). The corresponding test results are shown in table 10,
as a result: from table 10, it can be seen that: indices related to bone marrow suppression in mice in the Cyclophosphamide (CTX) experimental group compared to the blank control group: white blood cells, red blood cells, platelets and hemoglobin are all reduced in the bodies of mice to different degrees, wherein the reduction of the white blood cells is most obvious; and due to the protection effect of the fullerene, the amounts of white blood cells, red blood cells, platelets and hemoglobin of the mice in the CTX + fullerene oral emulsion experimental group are greatly improved compared with those of a Cyclophosphamide (CTX) experimental group, and related indexes are closer to the values of normal mice along with the prolonging of time. Meanwhile, compared with oral oil, the oral emulsion has better protective effect on bone marrow suppression. Shows that: the fullerene oral emulsion has more obvious protective effect on the mouse bone marrow suppression caused by the chemotherapeutic drug CTX.
TABLE 10 white blood cell count, red blood cell count, platelet count, hemoglobin assay data
Experimental example six test of ability of fullerene emulsion of the present invention to scavenge hydroxyl radicals
The testing of the ability of the emulsion to scavenge hydroxyl radicals was performed using DMPO-OH spin trapping. And (3) irradiating hydrogen peroxide by using ultraviolet light to generate free radicals, then adding the fullerene emulsion into the fullerene emulsion, and judging the capacity of the fullerene emulsion for removing the free radicals by comparing the intensity of ESR signals of the hydroxyl free radicals before and after the fullerene emulsion is added. As a result, as shown in fig. 1, when the fullerene emulsion was added to the test system, the hydroxyl radical in the system was almost completely quenched.
Test example seven Fullerene emulsion of the present invention has anti-oxidation effect
Evaluating the antioxidant protection effect of the fullerene emulsion by selecting vascular endothelial cells: firstly, incubating human endothelial cells and a fullerene emulsion together for 5 hours, then centrifuging, removing supernatant, adding a culture medium into a culture dish, then adding hydrogen peroxide with the concentration of 100umol/L, continuing to incubate for 12 hours, and then analyzing the cells. As shown in fig. 2, the morphology of the cells in the model group (hydrogen peroxide damaged group) and the blank control was substantially consistent, indicating that the fullerene emulsion exhibited excellent protective efficacy against the cells.
Experimental examples eight particle size measurement of the oral emulsion of the present invention
The fullerene emulsion is diluted by 100 times by water, and then the particle size of the fullerene emulsion is detected by a dynamic light scattering analyzer, as shown in fig. 3, the particle size of the fullerene emulsion is basically maintained between 130-180 nm.
Test example nine: the oral emulsion has effect in inhibiting tumor
Experiments were carried out using the fullerene emulsion of example 1
Animal strain: balb/c female mouse, 5 weeks, the weight between 16-20 g;
tumor model: mouse liver cancer H22 tumor strain;
grouping experiments: the groups were randomly divided into drug group A, drug group B and control group C, 6 of which were administered.
The administration mode comprises the following steps: (1) administering 1mg/ml fullerene emulsion to mice of drug group A orally at a dose of 200ul/d for 10 consecutive administrations; (2) administering 1.2mg/ml fullerene oil (patent WO2013/025180a1) orally, 200ml/kg/d, to mice of drug group B for 10 consecutive doses; (3) control group C: saline (Saline);
orally taking; administration dose:
the experimental method comprises the following steps: subcutaneously inoculating 100 μ L of H22 liver cancer cells with the concentration of 5 × 107/ml; the administration is started 24 hours after the inoculation, and the administration is continuously carried out for 10 times; and weighing the weight of the mouse every other day during the experiment, observing the growth condition of the tumor, finishing the experiment by 15 days after inoculation, weighing the tumor of the mouse, measuring the volume of the tumor, and calculating the tumor inhibition rate.
Table 11 the following results were obtained by the above anticancer method and tumor inhibition ratio calculation:
as can be seen from the comparison of Table 11 above, the fullerene oral emulsion of the present invention has better tumor inhibition efficiency than the fullerene oil product.
Example ten: fullerene oral emulsions for beneficial effects on parkinson's disease states
Wistar rat, body weight 180-. The experiment is divided into 5 groups, each half of male and female, the control group is not molded, and the rest groups are subjected to intragastric administration after two weeks of molding and are continuously administered for 6 weeks. The fullerene oral emulsion is divided into a high dose group (0.424mg/ml), a medium dose group (0.212mg/ml) and a low dose group (0.106mg/ml), the administration dose is 2ml, and an LPS damage model is adopted: apomorphine (0.5mg/kg) after subcutaneous injection can well simulate the behavioural and pathological changes of Parkinson's disease. The rotational behavior towards the healthy side was induced after 5-15 minutes of injection, and the behavior of the control rats was changed. The number of revolutions of the rats in the PD group is increased along with the increase of the molding time, the number of revolutions of the rats in the administration group is reduced along with the extension of the molding time, and the reduction of the number of revolutions of the rats in the high-dose group is more obvious. Especially, the number of revolutions of rats in the high dose group and the middle dose group is remarkably different from that in the PD group (P is less than 0.05) in the 5 th and the 6 th weeks, and the data in the table 2 can show that the fullerene injection emulsion has remarkable effect on the LPS-induced senile dementia
TABLE 12 rat spin behavior Change (rpm)
In conclusion, the invention has the following beneficial effects:
1. the inventors found that in the preparation of a fullerene emulsion, no homogeneous emulsion was obtained regardless of the homogeneity of fullerene, vegetable oil, and an emulsifier, and the emulsion was always in a suspended state. The emulsion prepared by homogenizing the fullerene oil and the emulsifier after the fullerene is prepared into the fullerene oil in advance can overcome the defects. The particle size of the emulsion can reach 50-300nm through monitoring by a dynamic light scattering analyzer.
2. According to the invention, the fullerene is prepared into the emulsion for the first time, and the oral fullerene emulsion has high bioavailability and stability by selecting proper components such as the vegetable oil emulsifier, proper process parameters and the like; the fullerene emulsion for oral administration is prepared, and the side effect of pure fullerene oil in the form of preparation is reduced. When the fullerene oil solution is an oral liquid, the dosage of the fullerene emulsion is easier to accurately quantify than that of the fullerene oil solution, the oil solution can be adhered to the wall of a container, and the emulsion cannot be hung on the wall. If the oil agent is encapsulated for accurate dosing, the side effect becomes greater if the patient takes too many capsule shells. The emulsion can be directly drunk smoothly, and the side effect of excessive medicinal preparation auxiliary materials is reduced.
3. The fullerene oil and the polyoxyethylene castor oil are two key components in the fullerene oral emulsion, and particularly the polyoxyethylene castor oil is an emulsifier which is selected to have the best solubility on fullerene.
4. The fullerene emulsion has the effects of clearing free radicals in human bodies, relieving body injury, resisting aging and the like, and has no side effect.
5. The invention also provides the function of the oral fullerene emulsion in preparing the tumor treatment medicine. In particular to the application in preparing the medicine for treating bone marrow suppression. Compared with oral oil, the injection emulsion has better protective effect on bone marrow suppression.
6. The oral emulsion prepared by the invention has excellent performances in the aspects of inhibiting tumors, relieving Parkinson's disease symptoms and removing hydroxyl free radicals.
7. The fullerene emulsion has good dispersion effect and large effective surface area, and is beneficial to the release, dissolution and absorption of medicaments; the emulsion contains emulsifier, has surface activity, and can improve gastrointestinal mucosa performance and promote drug absorption; after being absorbed, the grease in the emulsion can promote bile secretion, increase the flow rate of blood and lymph fluid and be beneficial to the dissolution and absorption of medicaments; the oil in the emulsion is digested to generate linoleic acid and oleic acid, which can inhibit gastrointestinal peristalsis and prolong the retention time of the medicine in small intestine; the oleaginous substances in the emulsion may also be transported and absorbed through the lymphatic system.
8. The fullerene emulsion prepared by the invention is dried and then prepared into solid preparations such as granules, capsules, tablets and other dosage forms, and the solid preparations are favorable for storage and transportation, are convenient to carry and are more favorable for patients to use conveniently.
9. The emulsion prepared by the invention adopts the emulsifier with strong emulsifying capacity and low cost, reduces the production cost and is beneficial to industrialized production.
Drawings
Figure 1 is a graph of the ability of an oral fullerene emulsion according to the present invention to scavenge hydroxyl radicals.
Fig. 2 is a graph of the ability of an oral fullerene emulsion according to the present invention to protect cells against oxidation.
Fig. 3 is particle size DLS data for an oral fullerene emulsion according to the present invention.
Detailed Description
The following detailed description of the present invention is provided in conjunction with the accompanying drawings, but it should be understood that the scope of the present invention is not limited to the specific embodiments.
Throughout the specification and claims, unless explicitly stated otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or component but not the exclusion of any other element or component.
Example 1C 70 Fullerene oil
Ball-milling and thinning fullerene powder C70 for 0.05-1 mu m, mixing thinned fullerene powder 1g with soybean oil 20g, placing the mixture in a ball mill for 500 r/min, ball-milling for 8h to obtain fullerene oil suspension, heating the fullerene oil suspension to 40 ℃, carrying out nitrogen protection, stirring for 12h, centrifuging, and filtering to obtain fullerene oil solution.
Example 2C 60 Fullerene oil
Ball-milling and thinning fullerene powder C60 for 0.05-1 mu m, mixing thinned fullerene powder 5g with soybean oil 100g, placing the mixture in a ball mill for 700 r/min, ball-milling for 12h to obtain fullerene oil suspension, heating the fullerene oil suspension to 50 ℃, carrying out nitrogen protection, stirring for 24h, centrifuging, and filtering to obtain fullerene oil solution.
Example 3C 76 Fullerene oil
Ball milling and thinning the fullerene powder C76 by 0.05-1 mu m, mixing the thinned fullerene powder 0.1 with 10g of prinsepia utilis royle oil, placing the mixture in a ball mill for 1000 r/min, ball milling for 20h to obtain fullerene oil suspension, heating the fullerene oil suspension to 60 ℃, carrying out nitrogen protection, stirring for 36h, centrifuging and filtering to obtain fullerene oil solution.
Example 4 Gd @ C82 Fullerene oil
Ball milling and thinning the fullerene powder Gd @ C82 for 0.05-1 mu m, mixing 10g of thinned fullerene powder with 40g of tea oil, placing the mixture in a ball mill for 500-1000 revolutions per minute, ball milling for 8-20h to obtain fullerene oil suspension, heating the fullerene oil suspension to 40-60 ℃, protecting with nitrogen, stirring for 12-72h, centrifuging, and filtering to obtain the fullerene oil solution.
Example 5C 60 Fullerene oil
Ball-milling and thinning fullerene powder C60 for 0.05-1 mu m, mixing 3g of thinned fullerene powder with 3g of olive oil, placing the mixture in a ball mill for 500 r/min, ball-milling for 80h to obtain fullerene oil suspension, heating the fullerene oil suspension to 40 ℃, carrying out nitrogen protection, stirring for 12h, centrifuging, and filtering to obtain fullerene oil solution.
Example 6C 60 Fullerene oil
Ball-milling and thinning fullerene powder C60 for 0.05-1 mu m, mixing 3g of thinned fullerene powder with 3g of olive oil, placing the mixture in a ball mill for 500 r/min, ball-milling for 80h to obtain fullerene oil suspension, heating the fullerene oil suspension to 40 ℃, carrying out nitrogen protection, stirring for 12h, centrifuging, and filtering to obtain fullerene oil solution.
Example 7C 76 Fullerene oil
Ball-milling and thinning fullerene powder C76 for 0.05-1 mu m, mixing 3g of thinned fullerene powder with 45g of castor oil, placing the mixture in a ball mill for 500 r/min, ball-milling for 80h to obtain fullerene oil suspension, heating the fullerene oil suspension to 40 ℃, carrying out nitrogen protection, stirring for 12h, centrifuging, and filtering to obtain fullerene oil solution.
Example 8C 60 Fullerene oil
Ball-milling and thinning fullerene powder C60 for 0.05-1 mu m, mixing thinned fullerene powder 5g with castor oil 25g, placing the mixture in a ball mill for 500 r/min, ball-milling for 80h to obtain fullerene oil suspension, heating the fullerene oil suspension to 40 ℃, stirring for 12h under the protection of nitrogen, centrifuging, and filtering to obtain fullerene oil solution.
Example 9C 70 Fullerene oil
Ball-milling and thinning the fullerene powder C70 by 0.05-1 mu m, mixing 1g of thinned fullerene powder with 15g of olive oil, placing the mixture in a ball mill for 500 r/min, ball-milling for 80h to obtain fullerene oil suspension, heating the fullerene oil suspension to 40 ℃, carrying out nitrogen protection, stirring for 12h, centrifuging, and filtering to obtain fullerene oil solution.
Example 10C 60 Fullerene emulsion
Weighing polyoxyethylene castor oil 180g, soybean phospholipid 160g, adding into fullerene C60 oil 800g and sodium citrate 3g, preheating to 60 deg.C, dispersing in 7000rmp, and stirring for 5min to obtain oil phase; supplementing 4000g of deionized water, preheating to 60 ℃, uniformly stirring by a dispersion machine at 5000rmp for 5min to obtain a water phase, slowly adding an oil phase into the water phase at 60 ℃ by a dispersion machine at 9000rmp for 10min to disperse and emulsify to obtain a primary emulsion, naturally cooling the temperature of the primary emulsion to room temperature, putting the primary emulsion into a high-pressure homogenizer, homogenizing for 4 times at 50MPa, fully dispersing by the dispersion machine, homogenizing for 4 times at 60MPa to obtain a stable fullerene emulsion, and adding a natural preservative and essence to prepare the fullerene emulsion.
EXAMPLE 11 Fullerene C70 emulsion
Weighing 90g of polyoxyethylene castor oil, 80g of soybean phospholipid and 2g of sodium citrate, adding the mixture into 400g of fullerene C70 oil, preheating to 60 ℃, stirring uniformly for 5min by using a dispersion machine 7000rmp to obtain an oil phase, supplementing 2000g of deionized water, slowly adding the oil phase into a water phase dispersion machine 9000rmp at 60 ℃ for 10min to disperse and emulsify to obtain primary emulsion, naturally cooling the temperature of the primary emulsion to room temperature, putting the primary emulsion into a high-pressure homogenizer, homogenizing for 4 times at 50MPa, separating to obtain stable fullerene emulsion, adding a natural preservative and essence, and blending the taste to obtain the fullerene emulsion.
EXAMPLE 12 Fullerene Gd @ C82 emulsion
Weighing 4.5g of polyoxyethylene castor oil, 5g of soybean phospholipid and 0.2g of sodium citrate, adding the mixture into 20g of fullerene Gd @ C82 oil phase, supplementing deionized water to 100g, fully dispersing by a dispersion machine, homogenizing for 4 times under 60MPa to obtain stable fullerene emulsion, adding a natural preservative and essence, and blending the flavors to obtain the fullerene emulsion.
Example 13: fullerene C76 emulsion
Weighing 45g of polyoxyethylene castor oil, 40g of soybean phospholipid and 2g of sodium citrate, adding into 200g of fullerene C76 oil phase, supplementing 1000g of deionized water, fully dispersing by a dispersion machine, homogenizing for 4 times under 50MPa to obtain stable fullerene emulsion, adding natural preservative and essence, and blending to obtain the fullerene emulsion.
Example 14: fullerene C84 emulsion
Weighing 45g of polyoxyethylene castor oil, 40g of soybean phospholipid and 2g of sodium citrate, adding into 200g of fullerene C84 oil phase, supplementing 1000g of deionized water, fully dispersing by a dispersion machine, homogenizing for 4 times under 60MPa to obtain stable fullerene emulsion, adding natural preservative and essence, and blending to obtain the fullerene emulsion.
Example 15: fullerene Gd @ C82 emulsion
Weighing 90g of polyoxyethylene castor oil, 80g of soybean phospholipid and 1.5g of sodium citrate, adding the mixture into 300g of fullerene Gd @ C82 oil phase, supplementing 2000g of deionized water, fully dispersing by a dispersion machine, homogenizing for 4 times under 60MPa to obtain stable fullerene emulsion, adding natural preservative and essence, and blending the taste to obtain the fullerene emulsion.
Example 16: fullerene C60 emulsion
Weighing 50g of polyoxyethylene castor oil, 40g of hydrogenated soybean phospholipid and 2g of sodium citrate, adding the materials into 150g of fullerene C60 oil phase, supplementing 1000g of deionized water, fully dispersing the materials by a dispersion machine, homogenizing the materials for 4 times under 50MPa to obtain stable fullerene emulsion, adding a natural preservative and essence, and blending the taste to obtain the fullerene emulsion.
Example 17: fullerene C70 emulsion
Weighing 45g of polyoxyethylene castor oil, 40g of egg yolk lecithin and 1g of sodium citrate, adding the mixture into 200g of fullerene C70 oil phase, supplementing 500g of deionized water, fully dispersing the mixture by a dispersion machine, homogenizing the mixture for 4 times under 50MPa to obtain stable fullerene emulsion, adding a natural preservative and essence, and blending the taste to obtain the fullerene emulsion.
Example 18: fullerene C84 emulsion
Weighing 80g of polyoxyethylene castor oil, 70g of soybean phospholipid and 2g of sodium dodecyl sulfate, adding into 180g of fullerene C84 oil phase, supplementing deionized water to 500g, fully dispersing by a dispersion machine, homogenizing for 4 times under 50MPa to obtain stable fullerene emulsion, adding natural preservative and essence, and blending to obtain the fullerene emulsion.
Example 19: fullerene C60 emulsion
Weighing 90g of polyoxyethylene castor oil, 80g of soybean phospholipid and 1.5g of sodium alginate, adding into 180g of fullerene C60 oil phase, supplementing 1000g of deionized water, fully dispersing by a dispersion machine, homogenizing for 4 times under 60MPa to obtain stable fullerene emulsion, adding natural preservative and essence, and blending to obtain the product.
Example 20: fullerene C70 emulsion
Weighing 180g of polyoxyethylene castor oil, 160g of soybean phospholipid and 4g of sodium citrate, adding into 800g of fullerene C70 oil phase, supplementing 4000g of deionized water, fully dispersing by a dispersion machine, homogenizing for 4 times under 50MPa to obtain stable fullerene emulsion, adding natural preservative and essence, and blending to obtain the fullerene emulsion.
Example 21: fullerene soft capsule
Mixing gelatin: glycerol: adding 0.4% of curcumin into water at a ratio of 2:1:2 to prepare molten gel, and carrying out the processes of pelleting, shaping, washing and rubbing, drying and drying pills, picking pills and the like on the fullerene emulsion and the molten gel to prepare the fullerene soft capsule.
Example 22: fullerene solid granule electuary
Adding auxiliary materials into the fullerene emulsion for granulation, and selecting sucrose powder: corn starch: calcium hydrogen phosphate ═ 1.3:1.1:1.4, preheated for 5 minutes in a rapid stirring granulator, granulated with a one-step granulation spray dryer to obtain solid granules-bagged.
Example 23: fullerene tablet
Specification 5mg
Example 23 Fullerene emulsion granule 50g, starch 200g, microcrystalline cellulose 200g, crospovidone 50g, lactose 1000g, purified water 1000g, magnesium stearate 20g, made into 10000 tablets.
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.
Claims (9)
1. An oral fullerene emulsion is characterized by comprising the following components in percentage by weight:
the emulsifier is soybean phospholipid and polyoxyethylene castor oil; the auxiliary emulsifier is sodium citrate; the weight ratio of the soybean lecithin, the polyoxyethylene castor oil and the sodium citrate is (4-5) to (4.5-5) to (0.2-0.3); the fullerene oil is prepared by ball-milling and thinning fullerene powder by 0.05-1 mu m, and mixing the thinned fullerene powder with vegetable oil; wherein the weight portion ratio of the fullerene to the vegetable oil is (0.1-10) to (10-40); the vegetable oil is at least one of olive oil, soybean oil and tea oil.
2. The oral fullerene emulsion according to claim 1, comprising the following components in percentage by weight:
3. an oral fullerene emulsion according to claim 1 or claim 2 wherein the size of the emulsion droplets in the emulsion is between 50 and 200 nm.
4. The oral fullerene emulsion according to claim 3, wherein the emulsion droplets have a particle size of 50-150 nm.
5. The oral fullerene emulsion according to claim 1, wherein the weight ratio of fullerene to vegetable oil is (1-5) to (15-25).
6. The oral fullerene emulsion according to claim 5, wherein the weight ratio of fullerene to vegetable oil is 1: 20.
7. A method of preparing an oral fullerene emulsion of claim 1 comprising the steps of:
step (1), fullerene oil: fully and uniformly mixing fullerene powder and vegetable oil, placing the mixture in a ball mill, carrying out ultrasonic treatment, stirring and heating to fully dissolve fullerene in the vegetable oil, and filtering to obtain fullerene oil;
step (2) oil phase preparation: mixing and preheating an emulsifier, an auxiliary emulsifier and fullerene oil, and placing the mixture in a dispersion machine to be uniformly stirred to obtain an oil phase;
adding water-soluble auxiliary materials into deionized water, mixing and preheating, and placing in a dispersion machine to be uniformly stirred to obtain a water phase;
and (4) slowly adding the oil phase into the water phase, placing the mixture into a dispersion machine, uniformly stirring and dispersing, and homogenizing under high pressure to obtain the oil-in-water fullerene emulsion.
8. The method of claim 7, wherein the method comprises the steps of:
ball-milling and thinning fullerene powder by 0.05-1 mu m, mixing the thinned fullerene powder with vegetable oil, placing the mixture in a ball mill for 500 plus 1000 revolutions per minute, carrying out ball milling for 8-20h to obtain fullerene oil suspension, heating the fullerene oil suspension to 0-60 ℃, carrying out nitrogen protection, stirring for 12-72h, centrifuging and filtering to obtain fullerene oil solution;
preheating the emulsifier, the co-emulsifier and the fullerene oil to 55-70 ℃, placing the mixture in a dispersion machine, and stirring the mixture at the rotating speed of 5000-;
step (3) adding water-soluble auxiliary materials into deionized water, preheating the mixture to 50-60 ℃, placing the mixture in a dispersion machine 3000 and 7000rmp for 8-15min, and uniformly stirring the mixture to obtain a water phase;
and (4) slowly adding the oil phase into the water phase at 50-60 ℃ for dispersing 7000-00 rmp, dispersing and emulsifying for 8-15min to obtain primary emulsion, naturally cooling the primary emulsion to room temperature, putting the primary emulsion into a high-pressure homogenizer, and homogenizing for 4-6 times under the pressure of 50-60MPa until the particle size of the emulsion is 150nm at 140-60 nm or the particle size of the emulsion is 50-100nm by microjet to obtain the emulsion.
9. Use of the oral fullerene emulsion according to claim 1 in the preparation of a medicament for treating tumors, parkinson's disease, bone marrow inhibitors or anti-aging medicaments for scavenging free radicals in vivo.
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| CN105596368A (en) * | 2016-02-01 | 2016-05-25 | 北京福纳康生物技术有限公司 | Fullerene olive oil composition and application thereof in treatment of Parkinson's disease |
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