阅读说明：本技术 富勒烯结构在制备治疗动脉粥样硬化的药物中的应用 (Application of fullerene structure in preparation of medicine for treating atherosclerosis ) 是由 王春儒 甄明明 *** 于 2018-09-05 设计创作，主要内容包括：本发明实施例涉及一种富勒烯结构在制备治疗动脉粥样硬化的药物中的应用,进一步涉及水溶性富勒烯结构在制备治疗动脉粥样硬化及其并发症的药物中的应用,所述水溶性富勒烯结构包括以下的至少一种：水溶性改性空心富勒烯、水溶性改性内嵌金属富勒烯、所述水溶性改性空心富勒烯和所述水溶性改性内嵌金属富勒烯的组合物、以上三者的可药用的酯或以上三者的可药用的盐。本发明中有效成分水溶性富勒烯结构能在相对较短的时间内有效的降低血脂、减小血管内膜上出现的斑块并能治疗动脉粥样硬化引起的肝肾损伤等并发症。(The embodiment of the invention relates to application of a fullerene structure in preparing a medicament for treating atherosclerosis, and further relates to application of a water-soluble fullerene structure in preparing a medicament for treating atherosclerosis and complications thereof, wherein the water-soluble fullerene structure comprises at least one of the following components: the organic solvent is selected from water-soluble modified hollow fullerene, water-soluble modified embedded metal fullerene, a composition of the water-soluble modified hollow fullerene and the water-soluble modified embedded metal fullerene, pharmaceutically acceptable esters of the three or pharmaceutically acceptable salts of the three. The water-soluble fullerene structure serving as the effective component can effectively reduce blood fat, reduce plaques on intima of blood vessels and treat complications such as liver and kidney injury caused by atherosclerosis in a relatively short time.)

1. Use of a water-soluble fullerene structure for the manufacture of a medicament for the treatment of atherosclerosis and its complications, said water-soluble fullerene structure comprising at least one of: the organic solvent is selected from water-soluble modified hollow fullerene, water-soluble modified embedded metal fullerene, a composition of the water-soluble modified hollow fullerene and the water-soluble modified embedded metal fullerene, pharmaceutically acceptable esters of the three or pharmaceutically acceptable salts of the three.

2. A pharmaceutical composition for treating atherosclerosis and its complications, comprising as an active ingredient at least one water-soluble fullerene structure selected from the group consisting of: the organic solvent is selected from water-soluble modified hollow fullerene, water-soluble modified embedded metal fullerene, a composition of the water-soluble modified hollow fullerene and the water-soluble modified embedded metal fullerene, pharmaceutically acceptable esters of the three or pharmaceutically acceptable salts of the three.

3. Use of a water-soluble fullerene structure according to claim 1 for the preparation of a medicament for the treatment of atherosclerosis and its complications or a pharmaceutical composition according to claim 2,

the water-soluble modified hollow fullerene comprises one or more selected from the group consisting of: (1) modifying the hollow fullerene body with a modified hollow fullerene with a hydrophilic group; (2) the hollow fullerene body is modified hollow fullerene wrapped by hydrophilic biological small molecules; (3) a modified hollow fullerene having a hollow fullerene body supported by a biocompatible carrier material; (4) a water-soluble hollow fullerene supermolecule system formed by self-assembly of a hollow fullerene body;

the water-soluble modified endohedral metallofullerene comprises one or more selected from the group consisting of: (1) modifying the modified embedded metal fullerene with hydrophilic groups on the embedded metal fullerene body; (2) the embedded metal fullerene body is modified embedded metal fullerene wrapped by hydrophilic biological micromolecules; (3) modified endohedral metallofullerenes in which the endohedral metallofullerene body is supported by a biocompatible carrier material; (4) the water-soluble embedded metal fullerene supermolecule system is formed by self-assembling the embedded metal fullerene body.

4. Use of a water-soluble fullerene structure according to claim 3 for the preparation of a medicament for the treatment of atherosclerosis and its complications or a pharmaceutical composition according to claim 3,

the hollow fullerene body comprises one or more than one hollow fullerene bodies with the general formula of C_2mM is more than or equal to 20 and less than or equal to 60, m is more than or equal to 30 and less than or equal to 60 optionally, and m is further optionally 30 or 35 or 42;

the metal-embedded fullerene body comprises M @ C_2n、M₂@C_2n、[email protected]_2n、M₃[email protected]_2n、M₂C₂@C_2n、M₂[email protected]_2n、M₂[email protected]_2nAnd M_xA_3-x[email protected]_2nWherein: m, A each represents a metal element and M, A each is selected from any of Sc, Y and lanthanide metal elements, 20. ltoreq. n.ltoreq.60, optionally 30. ltoreq. n.ltoreq.60, n being 41 or 30 or 35; x is more than or equal to 0 and less than or equal to 3.

5. Use of a water-soluble fullerene structure according to claim 3 for the preparation of a medicament for the treatment of atherosclerosis and its complications or a pharmaceutical composition according to claim 3, characterised in that the hydrophilic group comprises one or more of hydroxyl, carboxyl, thiol, amino and amino acid residues.

6. Use of a water-soluble fullerene structure according to claim 1 for the preparation of a medicament for the treatment of atherosclerosis and its complications or a pharmaceutical composition according to claim 2,

the general formula of the water-soluble modified hollow fullerene is C_2a(OH)_b(ii) a A is more than or equal to 20 and less than or equal to 60, optionally more than or equal to 30 and less than or equal to 60, and further optionally a is 30 or 35 or 42; 0<b is less than or equal to 50, and 0 is optional<b is less than or equal to 30, b is less than or equal to 10 and less than or equal to 30, b is less than or equal to 20 and less than or equal to 30, and further optional b is 13, 20, 22 or 24;

the general formula of the water-soluble modified metal-embedded fullerene is metalleyrene- (OH)_c(ii) a metalleyrene stands for the bulk of the endohedral metallofullerene, 0<c is less than or equal to 50, and optionally 0<c is less than or equal to 30, c is less than or equal to 10 and less than or equal to 30, c is less than or equal to 20 and less than or equal to 30, and further optional c is 13, 20, 22, 24 or 26;

further, the general formula of the water-soluble modified endohedral metal fullerene is M @ C_2d(OH)_eM is selected from rare earth metals, and optional rare earth metals are Gd or La; d is more than or equal to 20 and less than or equal to 60, and further optional d is 41 or 30 or 35; 0<e is less than or equal to 50, and optional 0<e.ltoreq.30, e.ltoreq.20, e.ltoreq.30, and optionally e 13, 20, 22, 24 or 26.

7. Use of a water-soluble fullerene structure according to claim 1 for the preparation of a medicament for the treatment of atherosclerosis and its complications or a pharmaceutical composition according to claim 2, wherein the water-soluble modified hollow fullerene and/or water-soluble modified endohedral metallofullerene are prepared by a process comprising the steps of: mixing the hollow fullerene body and/or the embedded metal fullerene body, hydrogen peroxide and an alkali solution, heating and reacting until the hollow fullerene body and/or the embedded metal fullerene body are completely dissolved, washing the obtained reaction liquid with ethanol, collecting precipitate, dialyzing the obtained precipitate to obtain water-soluble modified hollow fullerene and/or water-soluble modified embedded metal fullerene corresponding to the hollow fullerene body and/or the embedded metal fullerene body, wherein: the alkali solution comprises an aqueous sodium hydroxide solution and/or an aqueous potassium hydroxide solution.

8. Use of a water-soluble fullerene structure according to claim 7 for the preparation of a medicament for the treatment of atherosclerosis and its complications or a pharmaceutical composition according to claim 2, wherein the water-soluble modified hollow fullerene and/or water-soluble modified endohedral metallofullerene are prepared by a process comprising the steps of: (a) mixing 1-30% by mass of hydrogen peroxide, 8-80% by mass of alkali solution and the hollow fullerene body and/or the embedded metal fullerene body, wherein the volume ratio of 1-30% by mass of hydrogen peroxide to 10-80% by mass of alkali solution is 1-10:1, adding 20-500mg of the hollow fullerene body and/or the embedded metal fullerene body into every 10-200ml of mixed solution of hydrogen peroxide and alkali solution, stirring at 50-80 ℃ until the solid is completely dissolved, and filtering the reaction solution; (b) adding excessive ethanol with the concentration of 85% -100% into the obtained filtrate for washing, collecting precipitate, and dissolving the precipitate in water to obtain solution; (c) dialyzing the solution obtained in step (b).

9. Use of a water-soluble fullerene structure according to claim 1 for the preparation of a medicament for the treatment of atherosclerosis and its complications or a pharmaceutical composition according to claim 2, wherein the atherosclerosis comprises: atherosclerosis of aorta, atherosclerosis of coronary artery, atherosclerosis of brain, atherosclerosis of kidney, atherosclerosis of mesentery and atherosclerosis of lower limb, optionally atherosclerosis of aorta.

10. Use of a water-soluble fullerene structure according to claim 1 for the preparation of a medicament for the treatment of atherosclerosis and its complications or a pharmaceutical composition according to claim 2, wherein the treatment of atherosclerosis and its complications comprises: 1) so that dyslipidemia caused by atherosclerosis tends to be normal; 2) so that the renal index abnormality caused by the atherosclerotic nephropathy tends to be normal; 3) plaque in the artery is reduced.

Technical Field

The invention relates to the field of biological medicines, in particular to application of a fullerene structure in preparation of a medicine for treating atherosclerosis, and further relates to application of a water-soluble fullerene structure in preparation of a medicine for treating atherosclerosis and complications thereof.

Background

Atherosclerosis (AS) is one of the modern common diseases. The affected artery disease starts from bleeding and thrombosis of the intima, then fibrous tissue hyperplasia and calcareous deposition of the affected artery, and gradual disintegration and calcification of the middle layer of the artery cause thickening and hardening of the artery wall and narrowing of the blood vessel cavity to form atherosclerosis. Arterial lesions often involve large and medium muscle arteries, which supply tissues or organs that are ischemic or necrotic once they develop enough to occlude the lumen of the artery. Atherosclerosis also causes many complications, including liver and kidney damage and cardiovascular and cerebrovascular diseases, that are extremely harmful to human life health and safety.

Fullerene is another allotrope of carbon elements other than graphite, diamond and amorphous carbon, and refers to a cage-like structure composed of carbon atoms, the most abundant molecule of which is C₆₀Then is C₇₀、C₈₄Secondly a relatively low content of C₇₆、C₇₈、C₈₂And the like. In addition, because the interior of the carbon cage of the fullerene is of a cavity structure, different atoms, ions or atom clusters can be embedded into the cavity of the fullerene, and the formed material is called as the embedded fullerene, such as La @ C₆₀，[email protected]₆₀Indicates that La is embedded in C₆₀In the cage structure of (1), @ represents at, and the embedded meaning is expressed visually.

The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.

Disclosure of Invention

Object of the Invention

One of the purposes of the invention is to provide application of a water-soluble fullerene structure in preparing a medicament for treating atherosclerosis and complications thereof. It is a further object of the present invention to provide a pharmaceutical composition and method for treating atherosclerosis and its complications using water-soluble fullerene structures. The invention also aims to provide application of the water-soluble fullerene structure in preparing health-care products for improving atherosclerosis and complications thereof.

Technical scheme

In order to achieve the purpose of the invention, the embodiment of the invention provides the following technical scheme:

use of a water-soluble fullerene structure for the manufacture of a medicament for the treatment of atherosclerosis and its complications, said water-soluble fullerene structure comprising at least one member selected from the group consisting of: the organic solvent is selected from water-soluble modified hollow fullerene, water-soluble modified embedded metal fullerene, a composition of the water-soluble modified hollow fullerene and the water-soluble modified embedded metal fullerene, pharmaceutically acceptable esters of the three or pharmaceutically acceptable salts of the three.

The invention also provides a method for treating atherosclerosis and its complications, comprising the steps of: administering to a subject having atherosclerosis an effective amount of a water-soluble fullerene structure comprising at least one selected from the group consisting of: the organic solvent is selected from water-soluble modified hollow fullerene, water-soluble modified embedded metal fullerene, a composition of the water-soluble modified hollow fullerene and the water-soluble modified embedded metal fullerene, pharmaceutically acceptable esters of the three or pharmaceutically acceptable salts of the three.

The present invention also provides a pharmaceutical composition for treating atherosclerosis and its complications, comprising at least one water-soluble fullerene structure selected from the group consisting of: the organic solvent is selected from water-soluble modified hollow fullerene, water-soluble modified embedded metal fullerene, a composition of the water-soluble modified hollow fullerene and the water-soluble modified embedded metal fullerene, pharmaceutically acceptable esters of the three or pharmaceutically acceptable salts of the three.

The invention also provides application of the water-soluble fullerene structure in preparing health care products for improving atherosclerosis and complications thereof, wherein the water-soluble fullerene structure comprises at least one selected from the following components: the organic solvent is selected from water-soluble modified hollow fullerene, water-soluble modified embedded metal fullerene, a composition of the water-soluble modified hollow fullerene and the water-soluble modified embedded metal fullerene, pharmaceutically acceptable esters of the three or pharmaceutically acceptable salts of the three.

In another embodiment of the above use, method or pharmaceutical composition, the water-soluble modified hollow fullerene comprises one or more selected from the group consisting of: (1) modifying the hollow fullerene body with a modified hollow fullerene with a hydrophilic group; (2) the hollow fullerene body is modified hollow fullerene wrapped by hydrophilic biological small molecules; (3) a modified hollow fullerene having a hollow fullerene body supported by a biocompatible carrier material; (4) the water-soluble hollow fullerene supermolecule system is formed by self-assembling the hollow fullerene body.

In another embodiment of the above use, method or pharmaceutical composition, the water-soluble modified endohedral metallofullerene comprises one or more selected from the group consisting of: (1) modifying the modified embedded metal fullerene with hydrophilic groups on the embedded metal fullerene body; (2) the embedded metal fullerene body is modified embedded metal fullerene wrapped by hydrophilic biological micromolecules; (3) modified endohedral metallofullerenes in which the endohedral metallofullerene body is supported by a biocompatible carrier material; (4) the water-soluble embedded metal fullerene supermolecule system is formed by self-assembling the embedded metal fullerene body.

In another embodiment of the above use, method or pharmaceutical composition, the hydrophilic group comprises one or more of hydroxyl, carboxyl, thiol, amino and amino acid residues.

In another embodiment of the above application, method, pharmaceutical composition or health product, the amino acid residue refers to an incomplete amino acid remaining after a part of an amino acid molecule is lost when the amino acid is modified in an empty fullerene body or an endohedral metallofullerene body, that is: an amino acid residue is a portion of an amino acid molecule that is an incomplete amino acid. Any portion of the molecule lacking amino acids is counted as an amino acid residue, such as: the amino acid loses hydrogen on the amino group to be bonded with the hollow fullerene body or the embedded metal fullerene body, and the amino acid loses hydrogen or hydroxyl on the carboxyl group to be bonded with the hollow fullerene body or the embedded metal fullerene body. Alternatively, the amino acid residue is a water-soluble amino acid residue, such as: at least one of an alanine residue, a glycine residue, a serine residue, an arginine residue, a lysine residue, and a aspartic acid residue.

In another embodiment of the above use, method or pharmaceutical composition, the hydrophilic small biological molecule comprises at least one of an amino acid and a peptide chain.

In another embodiment of the above use, method or pharmaceutical composition, the biocompatible carrier material comprises: at least one of liposomes, proteins, polymeric micelles, and cell membrane carriers; optionally the protein comprises albumin or transferrin; optionally, the polymer micelle contains at least one of poly (glycolide-co-polyethylene glycol), polylysine and chitosan.

In another embodiment of the above application, method or pharmaceutical composition, the water-soluble modified hollow fullerene has a general formula C_2a(OH)_b(ii) a A is more than or equal to 20 and less than or equal to 60, optionally more than or equal to 30 and less than or equal to 60, and further optionally a is 30 or 35 or 42; 0<b is less than or equal to 50, and 0 is optional<b is less than or equal to 30, b is less than or equal to 10 and less than or equal to 30, b is less than or equal to 20 and less than or equal to 30, and further optional b is 13, 20, 22 and 24.

In another embodiment of the above application, method, pharmaceutical composition or health product, the water-soluble modified endohedral metallofullerene has the general formula metaloflulerene- (OH)_c(ii) a metalleyrene stands for the bulk of the endohedral metallofullerene, 0<c is less than or equal to 50, and optionally 0<c is less than or equal to 30, c is less than or equal to 10 and less than or equal to 30, c is less than or equal to 20 and less than or equal to 30, and further optional c is 13, 20, 22, 24 or 26.

In another embodiment of the above uses, methods or pharmaceutical compositions, the water-soluble modified endohedral metallofullerene has the general formula M @ C_2d(OH)_eM is selected from rare earth metals, and optional rare earth metals are Gd or La; d is more than or equal to 20 and less than or equal to 60, and further optional d is 41 or 30 or 35; 0<e is less than or equal to 50, and optional 0<e.ltoreq.30, e.ltoreq.20, e.ltoreq.30, and optionally e 13, 20, 22, 24 or 26.

In another embodiment of the above use, method or pharmaceutical composition, the water-soluble modified hollow fullerene is C₇₀(OH)₂₄·5H₂O; the water-soluble modified metal-embedded fullerene is Gd @ C₈₂(OH)₂₆。

The structural general formula C_2a(OH)_b、metallofullerene-(OH)_cAnd the general formula M @ C_2d(OH)_eRepresenting the substitution and connection of hydroxyl on the body of the hollow fullerene or the body of the embedded metal fullerene. In the general formula, b, c and e are all statistical average values calculated by detection.

In another embodiment of the above use, method or pharmaceutical composition, the water-soluble modified hollow fullerene is obtained by water-soluble modification of a hollow fullerene body, and the water-soluble modified endohedral metallofullerene is obtained by water-soluble modification of an endohedral metallofullerene body.

In another embodiment of the above use, method or pharmaceutical composition, the method of water solubility modification comprises any one of the following methods:

(1) the method for modifying hydroxyl comprises the following steps: mixing a hollow fullerene body and/or an embedded metal fullerene body, hydrogen peroxide and an alkali solution, heating and reacting until the hollow fullerene body and/or the embedded metal fullerene body are completely dissolved, filtering the reaction liquid, washing the obtained filtrate with ethanol, collecting precipitate, dialyzing the obtained precipitate to obtain a water-soluble hydroxyl derivative corresponding to the hollow fullerene body and/or the embedded metal fullerene body, wherein: the alkali solution comprises an aqueous sodium hydroxide solution and/or an aqueous potassium hydroxide solution.

Alternatively, the method of modifying a hydroxyl group comprises the steps of: mixing 1-30% by mass of hydrogen peroxide, 8-80% by mass of alkali solution and the hollow fullerene body and/or the embedded metal fullerene body, wherein the volume ratio of 1-30% by mass of hydrogen peroxide to 10-80% by mass of alkali solution is 1-10:1, adding 20-500mg of the hollow fullerene body and/or the embedded metal fullerene body into every 10-200ml of mixed solution of hydrogen peroxide and alkali solution, reacting at 50-80 ℃ (optional reaction time is 4-24h, stirring speed of reaction is 1000r/min) until all solids are dissolved, and filtering the reaction solution; adding excessive ethanol with the concentration of 85% -100% into the obtained filtrate for washing, collecting precipitate, and dissolving the precipitate in water to obtain solution; (c) dialyzing the solution obtained in step (b). Optionally, dialyzing until the conductivity of the solution at room temperature is less than 1 μ s/cm; further optionally, the dialysis treatment is followed by a step of freeze-drying in order to obtain the corresponding solid.

(2) The method for modifying the amino group on the surface comprises the following steps: the sodium hydroxide solution or potassium hydroxide solution used in the method for modifying a hydroxyl group is replaced with ammonia water.

(3) The physical coating method comprises the following steps: the hollow fullerene body and/or the embedded metal fullerene body is mixed with at least one of polyethylene glycol, polyvinylpyrrolidone and cyclodextrin, and the mixture is subjected to ball milling or ultrasonic treatment, so that a coated water-soluble fullerene structure corresponding to the body can be obtained, such as the hollow fullerene coated by polyethylene glycol and/or the embedded metal fullerene coated by polyethylene glycol, the hollow fullerene coated by polyvinylpyrrolidone and/or the embedded metal fullerene coated by polyvinylpyrrolidone.

In another embodiment of the above uses, methods or pharmaceutical compositions, the hollow fullerene body comprises one or more hollow fullerenes of the general formula C_2mM is more than or equal to 20 and less than or equal to 60, m is more than or equal to 30 and less than or equal to 60, and m is more than or equal to 30 or 35 or 42.

In another embodiment of the above uses, methods, or pharmaceutical compositions, the endohedral metallofullerene entity comprises M @ C_2n、M₂@C_2n、[email protected]_2n、M₃[email protected]_2n、M₂C₂@C_2n、M₂[email protected]_2n、M₂[email protected]_2nAnd M_xA_3-x[email protected]_2nWherein: m, A each represents a metal element and M, A each is selected from any of Sc, Y and lanthanide metal elements, 20. ltoreq. n.ltoreq.60, optionally 30. ltoreq. n.ltoreq.60, further optionally n is 41 or 30 or 35; x is more than or equal to 0 and less than or equal to 3. For example, the metal-embedded fullerene body is Gd @ C₈₂. N represents nitrogen, C represents carbon, S represents sulfur, O representsThe surface oxygen element and the lanthanide metal element comprise La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.

In another embodiment of the above use, method or pharmaceutical composition, the hollow fullerene body has a particle size of 0.7 to 1 nm; the particle size of the embedded metal fullerene body is 0.7-1 nm.

In another embodiment of the above use, method or pharmaceutical composition, the atherosclerosis comprises at least one of aortic atherosclerosis, coronary atherosclerosis, cerebral atherosclerosis, renal atherosclerosis, mesenteric atherosclerosis and lower limb atherosclerosis, optionally aortic atherosclerosis.

In another embodiment of the above use, method or pharmaceutical composition, the atherosclerotic complication comprises liver injury, kidney injury or cardiovascular and cerebrovascular disease.

In another embodiment of the above use, method or pharmaceutical composition, the treatment of atherosclerosis and its complications comprises: 1) reducing plaque in arteries; 2) so that dyslipidemia caused by atherosclerosis tends to be normal; 3) the renal index abnormality caused by atherosclerosis tends to be normal (the renal indexes include: urea nitrogen).

In another embodiment of the above use, method or pharmaceutical composition, the fullerene structure is administered in an amount of 1mg/kg/d to 500mg/kg/d, 1 to 10mg/kg/d, 1 to 20mg/kg/d, 1 to 30mg/kg/d, 5 to 500mg/kg/d, 5 to 300mg/kg/d or 5 to 100 mg/kg/d; the total dose of a specific subject is converted into the body weight. The treatment course can be 5 days to 30 days, and the medicine can be taken for a short time or a long time according to the state of illness; the administration mode of the effective components can be oral administration, intravenous injection or intraperitoneal administration.

The medicament or the pharmaceutical composition for the above use in another embodiment, the medicament or the pharmaceutical composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, or sterile packaged powder injections. The method of preparing the active ingredient into a medicament or pharmaceutical composition according to the present invention may be prepared by a method known to those of ordinary skill in the art such that the active ingredient is released, delayed or released, rapidly, or after administration to a subject, for example: the active ingredient may be mixed with, diluted with, or encapsulated in a carrier.

The medicament for use or the pharmaceutical composition as described above, in another embodiment, further comprises at least one pharmaceutically acceptable carrier, excipient or diluent, and some examples of suitable carriers, excipients and diluents include at least one of lactose, dextrose, sucrose, sorbitol, mannitol, starch, resins, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup (water syrup), methyl cellulose, methyl and propyl parabens, talc, magnesium stearate, and liquid paraffin.

Medicament in the above-mentioned application or the above-mentioned pharmaceutical composition in another embodiment, the medicament or the pharmaceutical composition may further comprise adjuvants such as lubricants, wetting agents, emulsifying and suspending agents, preservatives, sweeteners or flavoring agents.

The above-mentioned medicament for use or the above-mentioned pharmaceutical composition in another embodiment, the concentration of the water-soluble modified hollow fullerene and/or water-soluble modified endohedral metallofullerene in the preparation is 0.01-100 mg/mL.

In another embodiment of the above method, the subject comprises a mouse, guinea pig, rat, dog, rabbit, monkey, or human.

The term "treating" as used herein includes its generally accepted meaning which includes arresting, preventing, inhibiting, ameliorating, and slowing, stopping or reversing the development of the resulting symptoms or the desired pathology. As such, the invention encompasses both therapeutic and prophylactic administration.

The term "active ingredient" or "active ingredient water-soluble fullerene structure" used in the present invention refers to at least one of water-soluble modified hollow fullerene, water-soluble modified endohedral metallofullerene, a composition of the water-soluble modified hollow fullerene and the water-soluble modified endohedral metallofullerene, pharmaceutically acceptable esters of the above three, or pharmaceutically acceptable salts of the above three.

The term "effective amount" as used herein refers to an amount or dose of an active ingredient which, upon single or multiple administration to a patient, provides the desired effect in the patient diagnosed or treated. An effective amount can be determined by the attending diagnostician as one skilled in the art by known techniques and by observations made under similar circumstances. In determining the effective amount or dosage of the administered active ingredient, the attending diagnostician will consider a variety of factors including, but not limited to: mammalian species; volume, age, and general health; the particular disease involved; the degree or severity of involvement of the disease; the response of the individual patient; the specific compound administered; a mode of administration; the bioavailability properties of the administered formulation; the selected dosing regimen; use with drug therapy; and other related situations.

The term "hollow fullerene bulk" used in the present invention refers to hollow fullerene which is not water-soluble modified, i.e., a hollow fullerene raw material.

The term "bulk endohedral metallofullerene" used in the present invention refers to the endohedral metallofullerene without water-soluble modification, i.e., the endohedral metallofullerene raw material.

The disclosure of all ranges herein should be considered as disclosing all sub-ranges and all point values within the range. For example: the disclosure of 1-1000 should be considered to disclose the range of 1-200,200-300, etc., as well as 200, 300, 400, 500, 600, 700, 800, 900, and 100, etc.

Advantageous effects

1. The invention realizes water solubility of the hollow fullerene body and the embedded metal fullerene body, so that the hollow fullerene body and the embedded metal fullerene body can be transported to the liver and other organs to play a role along with blood circulation in a living body, and have higher bioavailability.

2. The diagnostic index of atherosclerosis is dyslipidemia, thickening and hardening of the arterial wall of a blood vessel, narrowing of the lumen of the blood vessel and even plaque appearing on the intima of the blood vessel, the treatment of atherosclerosis in the prior art needs long-term action of medicaments, and the structure of the water-soluble fullerene as an effective component in the invention can effectively reduce blood fat, reduce plaque appearing on the intima of the blood vessel in relatively low dosage and relatively short time and can treat complications such as liver and kidney injury caused by atherosclerosis.

Drawings

One or more embodiments are illustrated by the corresponding figures in the drawings, which are not meant to be limiting.

FIG. 1 shows C obtained in example 1₇₀(OH)_nThermogravimetric analysis and differential quotient thermogravimetric curves.

FIG. 2 shows C obtained in example 1₇₀(OH)_nElectron spin nuclear magnetic resonance (ESR) diagram of (1), wherein the smooth line indicates the blank control group and the non-smooth line indicates the addition of C₇₀(OH)_nThe experimental group of (1).

FIG. 3 is a graph of model group mice and C4 weeks after administration₇₀(OH)_nBlood lipid changes in experimental mice.

FIG. 4 is a graph of model group mice and C2 weeks after administration₇₀(OH)_nThe catalase content of the experimental mice was varied.

FIG. 5 is a group of model mice and C2 weeks after administration₇₀(OH)_nThe content of malondialdehyde in the experimental mice was varied.

FIG. 6 is a graph of model group mice and C4 weeks after administration₇₀(OH)_nChanges in urea nitrogen in experimental mice.

FIG. 7 is a graph of model group mice and C4 weeks after administration₇₀(OH)_nExperimental group mouse liver tissue HE staining pattern.

FIG. 8 shows model groups of mice and C4 weeks after administration₇₀(OH)_nExperimental group mice were stained for aortic root HE.

FIG. 9 shows model groups of mice and C4 weeks after administration₇₀(OH)_nGross staining pattern of experimental group mice.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. And any embodiment need not be construed as preferred or advantageous over other embodiments, unless expressly stated otherwise. 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.

Furthermore, in the following detailed description, numerous specific details are set forth in order to provide a better understanding of the present invention. It will be understood by those skilled in the art that the present invention may be practiced without some of these specific details. In some embodiments, methods, means, elements well known to those skilled in the art are not described in detail so as not to obscure the present invention. In some embodiments, materials, reagents, and the like used, unless otherwise specified, are commercially available.

Raw materials C used in the following examples₇₀The solid powder is purchased from Xiamen New Material science and technology Co., Ltd, and has a molecular weight of 840 and a purity of 99%.