CN115109069A - Stereospecific synthesis method of acetyldihydroartemisinin and application of acetyldihydroartemisinin in resisting atherosclerosis - Google Patents
Stereospecific synthesis method of acetyldihydroartemisinin and application of acetyldihydroartemisinin in resisting atherosclerosis Download PDFInfo
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- CN115109069A CN115109069A CN202210791166.4A CN202210791166A CN115109069A CN 115109069 A CN115109069 A CN 115109069A CN 202210791166 A CN202210791166 A CN 202210791166A CN 115109069 A CN115109069 A CN 115109069A
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- Prior art keywords
- acetyldihydroartemisinin
- dihydroartemisinin
- acetyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/20—Spiro-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Abstract
The invention discloses a stereospecific synthesis method of acetyldihydroartemisinin and new application in the field of cardiovascular of acetyldihydroartemisinin. The molecular formula of the acetyl dihydroartemisinin is C 17 H 26 O 6 The molecular weight is 326.39, and its stereoisomers exist, namely alpha-acetyldihydroartemisinin (structural formula shown in formula I) and beta-acetyldihydroartemisinin (structural formula shown in formula II). The new application is the application of the acetyldihydroartemisinin in preparing products for preventing and/or treating atherosclerosis related diseases. In vivo via ApoE-/-micePharmacodynamic research shows that the combination of acetyldihydroartemisinin and small-dose atorvastatin can inhibit the generation of aortic plaques in mice, and the pharmacodynamic result is equivalent to that of singly using large-dose atorvastatin. The compound medicine is mainly applied to preventing and treating patients and potential patients with atherosclerosis.
Description
Technical Field
The invention relates to the field of organic synthesis and biomedicine, in particular to a method for stereospecifically preparing alpha and beta type acetyldihydroartemisinin and application thereof in an anti-atherosclerosis effect.
Background
Atherosclerosis (AS) harms human health, and has a high disability rate and mortality rate in complications. The AS sick population has a large base number and a high growth speed, gradually tends to be younger and is more and more concerned by people. Statins are effective in reducing cardiovascular events, but leave a "residual risk" for cardiovascular events. The mechanism leading to this phenomenon is complex. Although people are continuously searching for breakthroughs in various aspects such AS identification of new risk factors, stricter blood lipid targets and development of new drugs, long-term management of AS is far from the point of importance due to the influence of factors such AS economic capacity, medical insurance coverage and lack of long-term management modes. Overall evaluation, the development of novel anti-atherosclerotic therapeutic or prophylactic agents that can be used for a long period of time has important clinical value.
Artemisinin (ART) is extracted from Artemisia annua L of Compositae, and has sesquiterpene lactone compound with peroxide bridge structure, and is used for treating malaria. In antimalarial drug research, the pharmaceutical property of artemisinin can be continuously optimized. On the premise of keeping the chemical structure of the peroxide bridge, the carbonyl on the lactone ring is reduced into hydroxyl to become Dihydroartemisinin (DHA), so that the bioavailability can be improved. On the basis of dihydroartemisinin, derivatives such as Artesunate (AST), Artemether (AM) and the like are designed and synthesized. DHA, AST and AM together constitute artemisinin drugs clinically applied in various countries in the world. The inventors believe that these three drugs are not ideal oral AS therapeutic or prophylactic agents. Therefore, the dihydroartemisinin is structurally modified, a stereospecific synthesis method of acetyl dihydroartemisinin (an artemisinin derivative, AcDHA) is established by adopting a classical acetylation reaction, the fat solubility is enhanced, the defect of poor solubility of artemisinin drugs is overcome, the stability is good, and the compound is potential to become a novel high-quality oral artemisinin drug. At present, no report related to the stereospecific synthesis method of the acetyldihydroartemisinin is seen domestically and internationally. Meanwhile, no report about the anti-atherosclerosis effect of the acetyldihydroartemisinin is found.
Disclosure of Invention
The invention aims to provide a stereospecific synthesis method of acetyldihydroartemisinin and a new application of acetyldihydroartemisinin.
The stereospecific synthesis method and the new application of the acetyldihydroartemisinin provided by the invention are (a) and/or (b) and/or (c) as follows:
(a) a stereospecific synthesis method of two epimers of the acetyldihydroartemisinin;
(b) the application of acetyldihydroartemisinin in preparing products for treating atherosclerosis related diseases;
(c) application of acetyldihydroartemisinin in preparing products for preventing atherosclerosis related diseases is provided.
The product may be a medicament or a pharmaceutical formulation.
The molecular formula of the acetyl dihydroartemisinin is C 17 H 26 O 6 The molecular weight is 326.39, and epimers thereof, namely alpha-acetyldihydroartemisinin (structural formula shown in formula I) and beta-acetyldihydroartemisinin (structural formula shown in formula II) exist.
The invention provides a preparation method of acetyl dihydroartemisinin, and provides a method for preparing the compound, and the preparation of the medicine containing the compound can be added with corresponding carrier materials, so that the compound is beneficial to absorption of organisms.
In the above applications, acetyldihydroartemisinin can be used as one of the effective ingredients in the preparation of a medicament or pharmaceutical preparation.
In the above applications, acetyldihydroartemisinin can be used as one of the active ingredients in the preparation of a medicament or pharmaceutical preparation.
The invention also provides a medicine or a medicine composition, and the active ingredients of the medicine or the medicine composition are acetyl dihydroartemisinin and statins. The medicine or the medicine composition contains the pharmaceutically acceptable auxiliary materials and one or more selected from carrier materials.
The medicament or the medicament composition has at least one of the following effects:
1) treating hyperlipidemia;
2) treating atherosclerosis-related diseases;
3) preventing atherosclerosis related diseases.
The medicine or the pharmaceutical composition can be prepared into pharmaceutical oral preparations such as tablets, capsules, dripping pills, powder, solutions, suspensions, emulsions, syrups, effervescent tablets, granules, liposomes, buccal tablets, freeze-dried powder injections and the like according to the conventional methods known by the technicians in the field, and can be common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle delivery systems.
In the above application, carrier material can also be added during preparation of the medicine. Carrier materials include, but are not limited to, water-soluble carrier materials (e.g., polyethylene glycol, polyvinylpyrrolidone, organic acids, etc.), sparingly soluble carrier materials (e.g., ethyl cellulose, cholesterol stearate, etc.), enteric carrier materials (e.g., cellulose acetate phthalate, and carboxymethylcellulose, etc.). The materials can be prepared into various dosage forms, including but not limited to tablets, capsules, dripping pills, powder, solutions, suspensions, emulsions, syrups, effervescent tablets, granules, liposomes, buccal tablets, films, freeze-dried powder injections and other medicinal oral preparations, which can be common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle delivery systems. In order to prepare the unit dosage form into tablets, various carriers well known in the art can be widely used. Examples of the carrier are, for example, diluents and absorbents such as starch, dextrin, sodium chloride, mannitol, sorbitol, erythrose, sucrose, glucose, lactose, urea, calcium carbonate, calcium sulfate, calcium hydrogen phosphate, light magnesium oxide, microcrystalline cellulose, aluminum silicate and the like; wetting agents and binders, such as distilled water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. Lubricants, for example, stearic acid, magnesium stearate, calcium stearate, talc, aerosil, hydrogenated vegetable oils, polyethylene glycols, sodium lauryl sulfate, and the like. The tablets may be further formulated into coated tablets such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets; effervescent tablets, chewable tablets, dispersible tablets, sustained release tablets, controlled release tablets and the like. In order to prepare the unit dosage form into granules, various carriers known in the art can be widely used. Examples of carriers are, for example, diluents such as starch, sucrose, lactose, dextrin and the like; adhesives such as starch slurry, cellulose derivatives, and the like. In order to prepare the dosage form of a unit dosage form into dripping pills, various carriers well known in the art can be widely used. Examples of carriers are, for example, water-soluble bases such as polyethylene glycol 6000, polyethylene glycol 4000, poloxamer, glycerogelatin, polyhydroxyl (40) stearate, etc.; fat-soluble base such as stearic acid, glyceryl monostearate, hydrogenated vegetable oil, etc. In order to prepare a unit dosage form into a capsule, various carriers known in the art can be widely used. Examples of carriers are, for example, capsule shells, such as gelatin, plant cellulose and derivatives thereof, etc. The capsule can be further made into hard capsule, soft capsule, enteric capsule, sustained release capsule, controlled release capsule, etc. In order to prepare the unit dosage form into a liquid preparation such as a solution, a suspension, an emulsion, a syrup, etc., various carriers well known in the art can be widely used. Examples of the carrier are, for example, polar solvents such as water, glycerin and the like; semi-polar solvents such as ethanol, propylene glycol, and the like; non-polar solvents such as liquid paraffin, etc.; solubilizers such as polysorbates, polyoxyethylene fatty acid esters, etc.; cosolvents such as sodium benzoate and the like; cosolvents such as ethanol, propylene glycol, glycerol, and the like; suspending agents such as sorbitol, glycerol, acacia, sodium alginate, tragacanth, methylcellulose, sodium carboxymethylcellulose, carbomer, dextran, aluminum monostearate, and the like; wetting agents such as polyoxyethylene castor oil, poloxamers, etc.; thickening agents such as methylcellulose, sodium carboxymethylcellulose, sodium alginate, agar, xanthan gum, pectin, beeswax, glyceryl monostearate, stearyl alcohol, etc.; solubilizers such as polysorbates, local ethylene oxide fatty acid esters, etc.; emulsifying agent such as acacia, gelatin, pectin, etc. In addition, colorants, preservatives, flavors, flavorings, sweeteners or other materials may also be added to the pharmaceutical preparation, if desired.
The population base of atherosclerosis patients is large, the disability rate and the fatality rate of complications are high, the residual risk of cardiovascular events still remains while the cardiovascular events are effectively reduced by the statins, and the long-term management of atherosclerosis is far from the priority, so that the development of novel AS treatment or prevention medicines has a certain clinical application prospect. The inventor of the application thinks that the acetyl dihydroartemisinin as the ester derivative of the dihydroartemisinin can become a medicine with better oral activity than the artemisinin medicines on the market at present. No study on the stereospecific synthesis method of the acetyldihydroartemisinin exists at home and abroad, and no study on the anti-atherosclerosis effect of the acetyldihydroartemisinin exists. The invention researches and invents a stereospecific synthesis method of acetyldihydroartemisinin, and finds that the combined use of the acetyldihydroartemisinin and atorvastatin can enhance the drug effect of atorvastatin, thereby achieving the effect of resisting atherosclerosis and providing a new scheme for further developing a new generation of artemisinin derivatives and a novel anti-atherosclerosis drug.
The invention has the beneficial effects that:
the acetyl dihydroartemisinin is a derivative of dihydroartemisinin, has higher in-vivo biological activity than dihydroartemisinin, has better pharmaceutical property than artemisinin, and has the potential of being developed into oral drugs. The invention provides a method for preparing alpha/beta type acetyldihydroartemisinin in a stereospecific manner by utilizing a pharmaceutical chemical synthesis method based on the characteristic that acetyldihydroartemisinin has epimerization for the first time, and develops a novel oral artemisinin derivative.
Secondly, the invention discovers for the first time that the acetyldihydroartemisinin has a certain effect of resisting atherosclerosis, can enhance the effect of statins such as atorvastatin on resisting atherosclerosis, expands the adaptability of artemisinin compounds, provides a new strategy for treating cardiovascular diseases, and can also provide a new research idea and method for the research and development of new traditional Chinese medicines.
Thirdly, the invention evaluates the difference of the anti-atherosclerosis effect of two stereoisomers based on the characteristic that the acetyl dihydroartemisinin has epimerization for the first time, the plaque area percentage of the aortic arch of the combined group of the beta-acetyl dihydroartemisinin and the atorvastatin is less than that of the combined group of the alpha-acetyl dihydroartemisinin and the atorvastatin, and the beta-acetyl dihydroartemisinin is proved to be the dominant configuration.
Drawings
The above and other objects, features, advantages and industrial significance of this invention will be better understood upon reading this invention in conjunction with the accompanying drawings and the detailed description of the preferred embodiments of the invention.
FIG. 1 shows the hydrogen nuclear magnetic resonance spectrum of acetyldihydroartemisinin alpha body (500MHz, CDCl) 3 )；
FIG. 2 is the NMR carbon spectrum of alpha-acetyldihydroartemisinin (125MHz, CDCl) 3 )；
FIG. 3 is a NMR spectrum of acetyldihydroartemisinin beta (500MHz, MeOD);
FIG. 4 is a NMR carbon spectrum (125MHz, MeOD) of β -bodies of acetyldihydroartemisinin;
FIG. 5 is a schematic diagram showing the effect of combined use of acetyldihydroartemisinin and atorvastatin on ApoE gene knockout (ApoE-/-) mouse aortic plaques, wherein A is a normal group, B is a model group, C is a combined use of alpha-acetyldihydroartemisinin and atorvastatin, D is a combined use of beta-acetyldihydroartemisinin and atorvastatin, and E is a positive atorvastatin group;
FIG. 6 is a schematic diagram showing the effect of combined use of acetyldihydroartemisinin and atorvastatin on ApoE gene knockout (ApoE-/-) mouse aortic arch plaques, wherein A is a normal group, B is a model group, C is a combined use of alpha-acetyldihydroartemisinin and atorvastatin, D is a combined use of beta-acetyldihydroartemisinin and atorvastatin, and E is a positive atorvastatin group;
FIG. 7 shows the structural formula of alpha-acetyl dihydroartemisinin (shown in formula I) and the structural formula of beta-acetyl dihydroartemisinin (shown in formula II).
Detailed Description
The invention is described in detail below with reference to the figures and the specific embodiments. The following detailed description will assist those skilled in the art in further understanding the invention, but the invention is not intended to be limited in any way. It should be noted that the present invention is not limited to the specific technical solutions described in the above embodiments, and those skilled in the art can make appropriate modifications without departing from the invention, which falls into the protection scope of the present invention. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified.
Example 1: acetylation reaction for preparing alpha-and beta-acetyldihydroartemisinin
(1) Reaction equation for preparing alpha-acetyldihydroartemisinin:
and (3) experimental operation: dihydroartemisinin (284mg,1mmol) was dissolved in 2mL of dry pyridine at room temperature, 2mL of acetic acid was added, and after the reaction mixture was stirred at room temperature for 1h, 4mL of acetic anhydride was added. After stirring at room temperature for 1 hour, 5mg of 4-dimethylamino-pyridine (DMAP) was added thereto, and the mixture was reacted at 0 ℃ for 24 hours with stirring. The progress of the reaction was monitored by thin layer chromatography, and after completion of the reaction, the reaction solution was slowly poured into 10mL of ice-distilled water which was rapidly stirred. After the solution was cooled to room temperature, the solution was extracted 3 times with 20mL of ethyl acetate, the ethyl acetate layers were combined, the ethyl acetate layer was washed 1 time with saturated brine, the ethyl acetate solution was dried over anhydrous sodium sulfate overnight, filtered, and the solvent was evaporated under reduced pressure to give a crude product. Redissolving with methanol, and recrystallizing with methanol-water system to obtain pure compound 202.12mg with yield of 62%.
α -acetyldihydroartemisinin: white or nearly colorless granules or powders, ESI-QTOF-MS M/z 349.1678 [ M + Na [ ]] + ； 1 HNMR(500MHz,CDCl 3 )δ5.786(d,J＝9.5Hz,1H),5.438(s,1H),2.564(s,1H)； 13 CNMR(125MHz,CDCl 3 )δ169.94,104.61,92.04,91.67,80.28,51.78,45.44,37.45,36.41, 34.28,31.94,26.13,24.76,22.18,21.26,20.36,12.22.
(2) The reaction equation for preparing the beta-acetyldihydroartemisinin is as follows:
and (3) experimental operation: dihydroartemisinin (284mg,1mmol) was dissolved in 4mL of dry pyridine at room temperature, the reaction mixture was dissolved with stirring at room temperature, 2mL of acetic anhydride was added, and after dissolution with stirring, 15mg of 4-dimethylamino-pyridine (DMAP) was added, and the reaction was stirred at 0 ℃ for 24 hours. The progress of the reaction was monitored by thin layer chromatography, and after completion of the reaction, the reaction solution was slowly poured into 10mL of ice-distilled water which was rapidly stirred. After the solution was cooled to room temperature, the solution was extracted 3 times with 20mL of ethyl acetate, the ethyl acetate layers were combined, the ethyl acetate layer was washed 1 time with saturated brine, the ethyl acetate solution was dried over anhydrous sodium sulfate overnight, filtered, and the solvent was evaporated under reduced pressure to give a crude product. Redissolving with methanol, and recrystallizing and purifying with methanol-water system to obtain 237.98mg of pure compound with 73% yield.
Beta-acetyldihydroartemisinin: white or nearly colorless granules or powders, ESI-QTOF-MS M/z 349.1615[ M + Na [ ]] + ； 1 HNMR(500MHz,MeOD)δ6.090(d,J＝3.0Hz,1H),5.501(s,1H),2.712(m,1H)； 13 CNMR (125MHz,MeOD)δ171.55,105.61,95.96,90.15,81.74,53.86,45.36,38.57,37.28,35.71,31.17, 25.95,25.81,25.17,21.02,20.63,12.77.
Example 2: high fat feed feeding ApoE-/-mice to form an atherosclerosis model
Male C57BL/6 mice 6 and ApoE knockout (ApoE-/-) mice 24, 10 weeks old, were divided into 5 groups by random number table one week after adaptive feeding: the normal group, the model group, the alpha-acetyldihydroartemisinin and atorvastatin combined group, namely an alpha + positive drug group (acetyldihydroartemisinin alpha body 32.6mg/kg BW, atorvastatin 2.5mg/kg BW), the beta-acetyldihydroartemisinin and atorvastatin combined group, namely a beta + positive drug group (acetyldihydroartemisinin beta body 32.6mg/kg BW, atorvastatin 2.5mg/kg BW), and the positive atorvastatin group (5mg/kg BW), 6 in each group. Wherein the normal group is C57BL/6 mice, and standard feed is given; the remaining groups were ApoE-/-mice fed high fat diet (21% fat, 0.15% cholesterol, basal diet 78.85%) with the corresponding drug by gavage for 15 weeks. After 15 weeks, the mice were fasted without water deprivation for 12h, anesthetized with 20% urethane (0.1 ml) per mouse, the aorta and aortic arch were separated, oil red O staining was performed, the plaque area of the aortic arch was measured using Image J, and statistical analysis was performed.
The results show that the effect of the combination of acetyldihydroartemisinin and atorvastatin on the aortic and aortic arch plaques of ApoE-/-mice is schematically shown in FIGS. 5 and 6. The aortic plaque area of the alpha-acetyldihydroartemisinin and atorvastatin combined group and the beta-acetyldihydroartemisinin and atorvastatin combined group is obviously reduced compared with that of the model group and is equivalent to that of the positive medicine atorvastatin group, and therefore the effect of the acetyldihydroartemisinin on the enhancement of the effect of atorvastatin is shown. And the area percentage of plaques of the aortic arch of the beta-acetyldihydroartemisinin and atorvastatin combined group is less than that of the alpha-acetyldihydroartemisinin and atorvastatin combined group (shown in the table 1), which indicates that the beta-acetyldihydroartemisinin is in a dominant configuration.
TABLE 1 percentage of aortic arch plaque area in each group of mice
* P<0.05, compared to a model set; **** P<0.0001, compared to model group.
In conclusion, the acetyl dihydroartemisinin has a certain effect of resisting atherosclerosis, can relieve atherosclerotic lesions and enhance the drug effect of atorvastatin when being used together with atorvastatin, and the beta-acetyl dihydroartemisinin is in a dominant configuration, so that a basis is provided for a new scheme of anti-atherosclerosis drug treatment in future.
Claims (8)
1. The stereospecific synthesis method and the new application of the acetyldihydroartemisinin (shown as formula I and formula II) provided by the invention are (a) and/or (b) and/or (c) as follows:
(a) a stereospecific synthesis method of two epimers of acetyl dihydroartemisinin;
(b) the application of acetyldihydroartemisinin in preparing products for treating atherosclerosis related diseases;
(c) the application of acetyl dihydroartemisinin in the preparation of products for preventing atherosclerosis related diseases;
the product may be a medicament or a pharmaceutical formulation.
2. Use according to claim 1, characterized in that: the stereospecific synthesis method of two epimers of the acetyl dihydroartemisinin is a stereospecific synthesis method of alpha-acetyl dihydroartemisinin and beta-acetyl dihydroartemisinin.
3. Use according to claim 1, characterized in that: the acetyl dihydroartemisinin is alpha-acetyl dihydroartemisinin and beta-acetyl dihydroartemisinin.
4. Use according to any one of claims 1 to 3, characterized in that: the product is any one of pharmaceutically acceptable preparations.
5. A medicine or pharmaceutical composition comprises active ingredients of formula I, acetyldihydroartemisinin shown in formula I and statins; the medicament or the medicament composition has at least one of the following effects:
1) treating hyperlipemia
2) Treating atherosclerosis-related diseases;
3) preventing atherosclerosis related diseases.
6. The drug or pharmaceutical composition of claim 5, wherein: the acetyl dihydroartemisinin is alpha-acetyl dihydroartemisinin and beta-acetyl dihydroartemisinin.
7. The drug or pharmaceutical composition of claim 5, wherein: the statins are lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and other marketed or non-marketed hydroxymethyl glutaryl coenzyme A reductase inhibitors and pharmaceutically acceptable salts thereof.
8. A medicament or pharmaceutical composition according to any one of claims 5 to 7, characterized in that: the medicine or the medicine composition is any pharmaceutically acceptable dosage form, comprises medicinal oral preparations such as tablets, capsules, dripping pills, powder, solutions, suspensions, emulsions, syrups, effervescent tablets, granules, liposomes, buccal tablets, freeze-dried powder injections and the like, and can be at least one of common preparations, sustained release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.
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| CN116370715A (en) * | 2023-05-10 | 2023-07-04 | 首都医科大学附属北京口腔医院 | Shapable porous biological composite bone filling material containing statin drugs and preparation method thereof |
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| EP0974594A1 (en) * | 1998-07-14 | 2000-01-26 | The Hong Kong University of Science & Technology | Artemisinin derivatives as anti-infective agent |
| CN103230392A (en) * | 2013-04-10 | 2013-08-07 | 上海交通大学 | Purposes of artemisinin compounds in preparing anti-atherosclerotic medicaments |
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| EP0974594A1 (en) * | 1998-07-14 | 2000-01-26 | The Hong Kong University of Science & Technology | Artemisinin derivatives as anti-infective agent |
| CN103230392A (en) * | 2013-04-10 | 2013-08-07 | 上海交通大学 | Purposes of artemisinin compounds in preparing anti-atherosclerotic medicaments |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116370715A (en) * | 2023-05-10 | 2023-07-04 | 首都医科大学附属北京口腔医院 | Shapable porous biological composite bone filling material containing statin drugs and preparation method thereof |
| CN116370715B (en) * | 2023-05-10 | 2024-05-17 | 首都医科大学附属北京口腔医院 | Shapable porous biological composite bone filling material containing statin drugs and preparation method thereof |
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