CN106539805B - A kind of application of ursolic acid-Aspirin Conjugate in the drug of preparation reducing blood lipid - Google Patents
A kind of application of ursolic acid-Aspirin Conjugate in the drug of preparation reducing blood lipid Download PDFInfo
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- CN106539805B CN106539805B CN201610933000.6A CN201610933000A CN106539805B CN 106539805 B CN106539805 B CN 106539805B CN 201610933000 A CN201610933000 A CN 201610933000A CN 106539805 B CN106539805 B CN 106539805B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
- A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
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Abstract
The present invention relates to purposes of the ursolic acid derivative of Formulas I in the drug that preparation reduces blood lipid.Common pharmaceutical dosage form technology can be used, oral tablet such as tablet, lozenge, water or the oil suspension of clinical use, dispersible agent or granula, emulsion, hard capsule or soft capsule, solution, syrup and elixir etc. can be prepared into.The mouse hyperlipidemia model test result of foundation shows that the compound formulation has the function of inhibiting and reducing blood lipid, can prepare the drug of the treatment for hyperlipidemia.
Description
Technical field
The present invention relates to the drug fields for belonging to reducing blood lipid, specifically, the present invention relates to ursolic acid and aspirin to be coupled
Application of the compound in blood lipid-lowering medicine.
Background technique
One of the main reason for cardiovascular disease is human death mainly includes coronary heart disease and cerebral apoplexy.85% coronary heart disease
It is and atherosclerosis and the direct phase of lipidosis, that is, dyslipidemia due to caused by coronary atherosclerosis
It closes, dyslipidemia shows as triglyceride in blood (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C)
One or more of it is horizontal increase or high-density lipoprotein cholesterol (HDL-C) is horizontal reduces, therefore blood is effectively reduced
Rouge plays a significant role treatment cardiovascular disease.
Ursolic acid (UA) is also known as malol, ursolic acid molecular formula C30H48O3, it is from the evergreen sprawling shrub black bearberry of Ericaceae
A kind of pentacyclic triterpenoid of middle extraction.It is more with calm, anti-inflammatory, antibacterial, anti-diabetic, antiulcer, reduction blood glucose etc.
Kind biological effect.Ursolic acid is distributed in plant kingdom than wide, such as Chinese medicine hawthorn, Fructus Corni, oldenlandia diffusa, cape jasmine, vehicle
Before, in Prunella vulgaris all contain ursolic acid, it is combined into the formal distribution of glycosides in plant in a free form or with sugar.Because it is day
Right compound shows biggish clinical application potentiality so its toxic side effect is small.
Aspirin (Aspirin, abbreviation ASA) has applied a century, becomes one of three big classical drugs in medical history, until
It is modern it be still most widely used antipyretic, analgesia and anti-inflammatory agent in the world, and as the standard for comparing and evaluating other drugs
Preparation.Have the function of antithrombotic in vivo, it can inhibit the release of blood platelet to react, inhibit the aggregation of blood platelet, this with
The reduction that TXA2 is generated is related.Clinically for preventing the breaking-out of cardiovascular and cerebrovascular disease.Discovered in recent years its to treatment coronary heart disease,
Colon cancer, breast cancer etc. are also helpful.But find that aspirin has the side effects such as upset,gastro-intestinal, bleeding in clinical practice,
To affect it further in clinical extensive use.Structure of modification is carried out to drug, improves the physicochemical property of drug, into one
Step improves its drug effect and overcomes its toxic side effect simultaneously, is a kind of common prodrug design strategy.Inventor seminar is in recent years
A large amount of research work is done to the structure of modification aspect of ursolic acid, ursolic acid derivative used in this invention is exactly
By the esterification of ursolic acid and aspirin, improve ursolic acid physicochemical property, the experiment proved that its bioavilability obtains
Greatly improve, and ASP-UA conjugate to the IC50 of breast cancer cell MCF-7 at 70 μM or so, and UA is in 30-40
Between μM (105111271 A of patent CN), the effective feature of ASP-UA low toxicity is shown.Ursolic acid has the work for reducing blood glucose
With, aspirin has the function of antithrombotic, and in recent years studies have reported that, Aspirin, which can reduce, suffers from cancer wind
Danger, but the two has the function of that reducing blood lipid there are no any report by the conjugate that esterification synthesizes.
Summary of the invention
As the compound of Formulas I is being prepared for reducing the purposes in the drug of blood lipid.
Specific application can prepare a kind of drug of lipid-loweringing, it is characterised in that compound comprising Formulas I (ursolic acid and Ah
The compound ASP-UA of department woods coupling).The present invention will safely and effectively ursolic acid and aspirin be obtained by esterification
Ursolic acid derivative (abbreviation ASP-UA, the preparation of the compound and characterization are referred to 105111271 A of patent CN),
Using the mouse hyperlipidemia model of foundation as object, the effect in drug body to mouse high in fat is investigated, the results showed that, ASP-UA can drop
Total cholesterol, triglycerides, low-density lipoprotein and the high-density lipoprotein of low mouse high in fat, prompt it to can be used as lipid-lowering medicine
Effect potentiality.Mouse hyperlipidemia model experiment show daily dose low (20mg/kg), in (40 mg/kg) can be more aobvious
The reduction blood lipid of work.
The compound can be processed into common formulations with pharmaceutic adjuvant, and such as tablet, lozenge, water or oil suspension can be dispersed
Agent or granula, emulsion, hard capsule or soft capsule, solution, syrup and elixir.Exquisite palatable pharmaceutical formulation in order to obtain, should
Pharmaceutical formulation may include one or more reagents for being selected from sweetener, corrigent, colorant and preservative.These excipient can be with
It is for example, diluent starch, dextrin, pregelatinized starch, Icing Sugar, lactose sodium saccharate；Wetting agent and adhesive, such as water, ethyl alcohol, shallow lake
Slurry, syrup；Disintegrating agent, such as dry starch, sodium carboxymethyl starch；Lubricant, such as magnesium stearate, talcum powder.
The present invention can also be by making active constituent be suspended in vegetable oil (such as peanut oil, soybean oil, sesame oil or olive oil)
Or oil-based suspension is made into mineral oil (such as liquid paraffin).Oil-based suspension may include thickener (such as cetanol, hard paraffin
Or beeswax).Sweetener and corrigent those of outlined above can be added, to obtain palatable oral preparation.It can be in drug
Antioxidant (such as ascorbic acid) anti-corrosion is added.
Make active constituent and dispersing agent or profit by adding water to the dispersible pulvis for being suitble to prepare aqueous suspension and granula
Humectant, suspending agent and the mixing of one or more preservatives.(such as lecithin, polyethylene oxide is hard for suitable dispersing agent or wetting agent
Resin acid ester and polyoxyethylene sorbitol monoleate) and suspending agent (such as sodium carboxymethylcellulose, methylcellulose and alginic acid
Sodium).It also may include other excipient, such as colorant, corrigent and sweetener.
Oil in water emulsion form also can be used in drug of the present invention.Oil mutually can be vegetable oil (such as peanut oil and soybean oil) or
Mineral oil (such as liquid paraffin) or their mixture.Suitable emulsion can be naturally occurring phosphatide (such as soybean, lecithin
Rouge), and the ester derived from fatty acid and hexitan or partial ester (such as Sorbitan Monooleate) and the partial ester and oxidation
The condensation product (such as polyoxy-ethylene sorbitan monoleate) of ethylene.Emulsion also may include sweetener and corrigent.It can
Syrup and elixir are prepared with sweetener (such as glycerol, propylene glycol, sorbierite or sucrose).Such preparation also may include wetting agent,
Preservative, flavoring agent and colorant.
Specific embodiment
In order to make content of the present invention easily facilitate understanding, With reference to embodiment to of the present invention
Technical solution is described further, but the present invention is not limited only to this.
Embodiment 1
66 kunming mices are randomly divided into 11 groups (every group 6): Normal group, hyperlipidemia model control group, UA low dosage
Control group, UA middle dosage control group, UA high dose control group, ASA low dosage control group, ASA middle dosage control group, ASA high agent
Measure control group, ASP-UA low dose group, ASP-UA middle dose group and ASP-UA high dose group.It raises on Normal group feeding basis
Material, remaining each group feed high lipid food, establish hyperlipidemia model.After hyperlipidemia model is successfully established, the basic, normal, high control of UA is given daily
The basic, normal, high control group of group, ASA, ASP-UA low dose group, the Kunming of ASP-UA middle dose group and ASP-UA high dose group are small
The corresponding drug solution of mouse stomach-filling, each amount are 0.3 mL.Kunming mice freely ingests and drinks water.
Testing index: (1) overnight fasting (24 h), next day heart extracting blood take serum after 15 d, with total cholesterol (TC),
Triglycerides (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C) kit detect each value, in microplate reader
The light absorption value that total cholesterol and triglycerides are detected at 510 nm, detects high-density lipoprotein and low-density lipoprotein at 546 nm
White light absorption value calculates mouse total cholesterol, triglycerides, high-density lipoprotein and low-density lipoprotein according to the formula of kit
Value, the results are shown in Table 1；(2) parameters such as whole blood viscosity, Plasma Viscosity are measured with fully automatic blood rheology instrument, as a result such as
Shown in table 2.
If 1 data of table are shown, the TC level of hyperlipidemia model control group mice serum is significantly higher than normal group mice serum
TC is horizontal, shows that the high cholesterol model of mouse has been set up.The TC that UA low dose group cannot reduce mouse high in fat is horizontal, with
The increase of dosage, UA have certain effect to the TC tool of mouse high in fat, and ASA low dosage and middle dosage can more reduce mouse high in fat
TC is horizontal, but the low dosage of ASP-UA and middle dose group can more significantly reduce the high cholesterol of mouse, and the work of low dosage
With more significantly.
Compared with hyperlipidemia model control group, the TG that the low dosage of ASP-UA group can reduce mouse high in fat is horizontal.
Compared with hyperlipidemia model group, the low of ASP-UA group, middle dose group ratio UA and ASA independent medication more can significantly reduce small
Mouse hdl level.
Compared with hyperlipidemia model group, the low of ASP-UA group, middle dose group ratio UA and ASA independent medication more can significantly reduce small
The low-density lipoprotein white level of mouse.
In conclusion ASP-UA is low, middle dosage can significantly reduce the indices of blood lipid, there is significant lipid-loweringing.
As shown in table 2, compared with normal rats, model group Mouse whole blood is viscous for influence of the ASP-UA to hemorheology
Degree, plasma viscosity significantly increase, and show: the change that hemorheological property reduces is presented in hyperlipidemic mice.Compared with model group,
The low dosage and middle dosage and the whole blood viscosity for being applied alone the high dose of UA group that can more reduce mouse high in fat of aspirin group is applied alone
And plasma viscosity, but the compound ASP-UA of the two coupling is low, middle dosage significantly reduces Mouse whole blood and plasma viscosity more.
Embodiment 2
With embodiment 1, mouse two weeks is persistently fed, after the last administration, mouse is put to death, adopted by overnight fasting (24 h)
Collect aorta sample, detects atherosclerotic plaques with image analytical method, the results are shown in Table 3.
As shown in table 3, model group aorta wall plaque area average out to 11.23%；Compared with model group, ASP-UA
Low, middle dosage is applied alone aspirin group to mouse aorta wall plaque area ratio or UA group is applied alone to be substantially reduced.
Embodiment 3
The g ASP-UA of 9 g~90 is taken, 10~100 g of dextrin, 200 g of pharmacy cornstarch are ground according to equal increments method
It is uniformly mixed, suitable 15% corn starch liquid is added, wet grain is made, cross 24 meshes, 40~45 DEG C of dryings, 24 mesh sieves add
Enter appropriate magnesium stearate to be uniformly mixed, is pressed into tablet, 0.4 g of slice weight with tablet press machine.
Embodiment 4
Take the g ASP-UA of 10 g~100, pharmacy cornstarch 300 g is uniform according to equal increments method ground and mixed, adds
Enter suitable 15% corn starch liquid and wet grain is made, crosses 24 meshes, 40~45 DEG C of dryings, 24 mesh sieves, particle packing, per small
Wrap 1 g.
Embodiment 5
The g ASP-UA of 9 g~90 is taken, 10~100 g of dextrin, 200 g of pharmacy cornstarch are ground according to equal increments method
Be uniformly mixed, suitable 15% corn starch liquid be added, wet grain is made, cross 16 meshes, particle in 40~60 DEG C of dry 30 min,
Using 16 mesh sieves, appropriate magnesium stearate is added, be uniformly mixed, by this particle be fitted into No. 0 hard capsule to get.
Claims (1)
1. as the compound of Formulas I is being prepared for reducing the purposes in the drug of blood lipid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610933000.6A CN106539805B (en) | 2016-10-25 | 2016-10-25 | A kind of application of ursolic acid-Aspirin Conjugate in the drug of preparation reducing blood lipid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610933000.6A CN106539805B (en) | 2016-10-25 | 2016-10-25 | A kind of application of ursolic acid-Aspirin Conjugate in the drug of preparation reducing blood lipid |
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| Publication Number | Publication Date |
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| CN106539805A CN106539805A (en) | 2017-03-29 |
| CN106539805B true CN106539805B (en) | 2019-07-09 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105111271A (en) * | 2015-08-03 | 2015-12-02 | 福州大学 | Ursolic acid-aspirin conjugate and application thereof in preparing drugs for preventing tumor metastasis |
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2016
- 2016-10-25 CN CN201610933000.6A patent/CN106539805B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105111271A (en) * | 2015-08-03 | 2015-12-02 | 福州大学 | Ursolic acid-aspirin conjugate and application thereof in preparing drugs for preventing tumor metastasis |
Non-Patent Citations (2)
| Title |
|---|
| 山楂中熊果酸的提取及其对小鼠的降血脂作用;林科等;《天然产物研究与开发》;20071231;第19卷;1052-1054 |
| 阿司匹林对高脂性动脉粥样硬化兔血脂及血小板聚集的影响;华轶男等;《苏州大学学报（医学版）》;20071231;第27卷(第6期);855-858 |
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