CN113456648B - New application of tanshinone IIA sodium sulfonate and its preparation - Google Patents

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation of tanshinone IIA sodium sulfonate and application thereof in preparing a medicine for treating cardiovascular diseases. The daily dosage of the tanshinone IIA sodium sulfonate is 50-200mg, pharmacological experiments prove that the tanshinone IIA sodium sulfonate can obviously reduce the contents of TC, TG and LDL-C in the serum of a hyperlipidemic mouse, improve the content of HDL-C, and the dissolution of tanshinone tablets and the dissolution of related substances meet the requirements of pharmacopoeia.

Description

New application of tanshinone IIA sodium sulfonate and its preparation

technical field

The invention relates to a new use of tanshinone IIA sodium sulfonate, in particular to the use of tanshinone IIA sodium sulfonate in preparing a drug for treating hyperlipidemia and/or a hypolipidemic drug, belonging to the technical field of medicine.

Background technique

Cardiovascular and cerebrovascular diseases are a general term for cardiovascular and cerebrovascular diseases, which generally refer to ischemic or hemorrhagic diseases of the heart, brain and whole body caused by hyperlipidemia, blood viscosity, atherosclerosis, hypertension, etc. disease. Cardiovascular and cerebrovascular disease is a common disease that seriously threatens the health of human beings, especially the middle-aged and elderly people over 50 years old. It has the characteristics of high morbidity, high disability rate and high mortality rate. There are still more than 50% of cerebrovascular accident survivors who cannot take care of themselves completely. The number of people who die of cardiovascular and cerebrovascular diseases in the world every year is as high as 15 million, ranking first among all causes of death.

Hyperlipemia, also known as hyperlipidemia, dyslipidemia, and hyperlipoproteinemia, refers to one or more lipids in plasma that are higher than normal, including cholesterol, triglycerides, phospholipids, and non-free fatty acids. , mostly due to abnormal fat metabolism or operation. What we usually call hyperlipidemia is called "dyslipidemia" and "hyperlipidemia" in modern medicine. Blood lipids are insoluble in water, combine with special proteins, and exist in the plasma in the form of lipoproteins, so dyslipidemia is mostly manifested as abnormal lipoproteins. Dyslipidemia is clinically divided into hypercholesterolemia (CH), hypertriglyceridemia (TG), mixed hyperlipidemia, and low-density lipoproteinemia. The damage of hyperlipidemia to the body is hidden, gradually developed and systemic. If there are too many lipids in the blood, they will gradually stay on the wall of the arterial blood vessel, which will thicken and harden the arterial blood vessel wall. , the formation of atherosclerosis, which induces a series of diseases, such as coronary heart disease, cerebral embolism, carotid artery stenosis and so on.

SUMMARY OF THE INVENTION

One of the objects of the present invention is to provide a new use of tanshinone IIA sodium sulfonate, that is, the use of tanshinone IIA sodium sulfonate in preparing a drug for treating hyperlipidemia and/or a drug for lowering blood lipids.

The above-mentioned tanshinone IIA sodium sulfonate can be prepared into a clinically acceptable dosage form directly or by adding pharmaceutical excipients.

Preferably, the clinically acceptable dosage forms include but are not limited to tablets, capsules, granules, and oral liquids.

The second purpose of the present invention is to provide the dosage of the above-mentioned sodium tanshinone IIA sulfonate, that is, the daily dosage of the sodium tanshinone IIA sulfonate is 50-200 mg; preferably, the daily dosage of the sodium tanshinone IIA sulfonate The usage amount is 80-160 mg; further preferably, the daily usage amount of the tanshinone IIA sodium sulfonate is 100-120 mg.

The third object of the present invention is to provide a tanshinone IIA sodium sulfonate tablet, and the tanshinone IIA sodium sulfonate tablet contains the following components:

Preferably, the tanshinone IIA sodium sulfonate tablet contains the following components:

Specifically, the filler is one or more of starch, dextrin, powdered sugar, lactose, microcrystalline cellulose, pregelatinized starch, anhydrous calcium hydrogen phosphate, mannitol, and sorbitol; preferably , the filler is a mixture of lactose, microcrystalline cellulose, and sorbitol; further preferably, the ratio of the lactose, microcrystalline cellulose, and sorbitol is 1:2-5:1-3; most preferably The ratio of the lactose, microcrystalline cellulose and sorbitol is 1:3.5:2.

Described adhesive is one or more of hypromellose, povidone K30, polyethylene glycol;

The disintegrating agent is one or more of low-substituted hypromellose, crospovidone or sodium starch glycolate;

Described glidant is one or more in fumed silica, silicon dioxide or talc;

The lubricant is one or more of magnesium stearate, sodium stearyl fumarate, talc, and micropowder silica gel.

Further, the tanshinone IIA sodium sulfonate tablet also contains a coating layer.

Preferably, the coating layer contains the following components:

Hydroxypropyl methylcellulose 70%-90%

Titanium dioxide 10%-30%

Magnesium Stearate 1%-2%.

Further preferably, the coating layer contains the following components:

Hydroxypropyl methylcellulose 75%-80%

Titanium dioxide 20%-30%

Magnesium Stearate 1%-1.5%.

Compared with the prior art, the present invention has achieved remarkable technical effects:

Pharmacological experiments confirmed that the serum levels of TC, TG and LDL-C in hyperlipidemic mice treated with tanshinone IIA sodium sulfonate were significantly decreased, and the HDL-C content was significantly increased, and the effect was comparable to the existing product simvastatin. In addition, the tanshinone IIA sodium sulfonate tablet prepared by the invention has good stability and rapid dissolution, and is suitable for clinical application.

Accompanying drawing 1: Comparison of the dissolution rate of each embodiment

specific embodiment

The present invention is further clarified below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. Modifications all fall within the scope defined by the appended claims of this application.

Embodiment 1 Tanshinone IIA sodium sulfonate tablet

Coating Layer:

Hydroxypropyl methylcellulose 700mg

Titanium dioxide 300mg

Magnesium Stearate 20mg.

Preparation process: take the prescribed amount of tanshinone IIA sodium sulfonate, lactose, microcrystalline cellulose, sorbitol hypromellose, low-substituted hypromellose, and silicon dioxide, and mix them uniformly by an equal amount incremental addition method, and dry granulation. , magnesium stearate is added to the mixed granules, and after mixing evenly, tableting, coating, and coating weight gain is 3%.

Example 2 Tanshinone IIA Sodium Sulfonate Tablets

Coating Layer:

Hydroxypropyl methylcellulose 900mg

Titanium dioxide 100mg

Magnesium Stearate 10mg.

The preparation process is described with reference to Example 1.

Example 3 Tanshinone IIA Sodium Sulfonate Tablets

Coating Layer:

Hydroxypropyl methylcellulose 750mg

Titanium dioxide 240mg

Magnesium Stearate 10mg.

The preparation process is described with reference to Example 1.

Example 4 Tanshinone IIA Sodium Sulfonate Tablets

Coating Layer:

Hydroxypropyl methylcellulose 800mg

Titanium dioxide 200mg

Magnesium Stearate 15mg.

The preparation process is described with reference to Example 1.

Comparative Example 1 Tanshinone IIA Sodium Sulfonate Tablets

Comparative Example 2 Tanshinone IIA Sodium Sulfonate Tablets

Coating Layer:

Hydroxypropyl methylcellulose 700mg

Titanium dioxide 300mg

Magnesium Stearate 20mg.

1. Stability inspection

Take the tanshinone IIA sodium sulfonate tablets obtained in Example 1-4 and Comparative Example 1-2, under the conditions of a constant temperature and humidity chamber with a temperature of 40 ° C and a relative humidity of 75 ± 5%, the accelerated test was carried out for 6 months, and respectively on 0 days. , 1 month and 6 months to detect related substances and contents, and compare the stability of different samples.

Table 1: Comparison of stability of samples at 40°C, 75% RH

As can be seen from Table 1, the tanshinone IIA sodium sulfonate tablet prepared by the present invention has good stability, and after the accelerated test, the related substances grow slowly, and the content is all above 98%; its stability is obviously better than that of Comparative Examples 1 and 2. .

2. Dissolution determination

The tablets obtained in Examples 1-4 were taken with 900 ml of water as the dissolution medium, the rotational speed was 50 rpm, and samples were taken at 5 min, 10 min, 15 min, 20 min and 30 min. Take an appropriate amount of the dissolution solution, filter it, discard the primary filtrate, and take the subsequent filtrate as the test solution; and replenish the dissolution medium with the same temperature and volume in time; another appropriate amount of tanshinone IIA sodium sulfonate reference substance is taken, and an appropriate amount is accurately measured. Dilute with dissolution medium to prepare a solution containing about 2 μg of tanshinone IIA sodium sulfonate per 1 ml. Precisely measure 50 μl of the test solution and the reference solution, respectively, inject them into the liquid chromatograph, record the chromatogram, and calculate the dissolution amount of each tablet.

Table 2 Dissolution of each group of tablets in aqueous solution

It can be seen from Table 2 that in the aqueous solution, implementations 1-4 all achieved more than 95% dissolution within 30 minutes, and the dissolution was stable and the dissolution effect was good; Comparative Example 1 had a faster dissolution, and Comparative Example 2 had a sudden release in the dissolution. phenomenon, the dissolution effect is not ideal.

3. Pharmacological experiments

In order to verify the efficacy of tanshinone IIA sodium sulfonate in the treatment of cardiovascular diseases, especially hyperlipidemia or blood lipid lowering, the inventors carried out relevant pharmacodynamic studies. It should be noted that the medicines selected in the following pharmacodynamic tests are the medicines obtained from the representative formulas of the present invention and the preparation methods thereof; the medicines obtained from other formulae and preparation methods contained in the present invention, the inventors also conducted the medicines. The experimental results show that the medicines obtained by other formulas and preparation methods have the same or similar effects, but due to space limitations, they are not exhaustive here.

In addition, the following pharmacodynamic experiments only use hyperlipidemia animal models as an example to verify the efficacy of the present invention. For other effects mentioned in the present invention, the inventor has also done relevant pharmacodynamic experiments. The experimental results show that the same or similar The effects, here, are no longer exhaustive.

The inventor wants to explain that the following experimental studies are carried out on the basis of the acute toxicity test and long-term toxicity test to prove the safety of the drug, and the doses in the experimental studies are all within the safe dose range.

1. The hypolipidemic effect of tanshinone IIA sodium sulfonate on hyperlipidemia mice

1 material

1.1 Animals:

Kunming mice, SPF grade, 18-22g, experimental animal license number: SYXK (Lu) 2018 0008, provided by Lunan Pharmaceutical Group Co., Ltd., and adaptively reared for one week before the experiment.

1.2 Drugs and reagents

1.2.1 Drugs

Tanshinone IIA sodium sulfonate tablet, prepared by the method described in Example 1

Simvastatin Tablets (Zunzi H20030705, Lunanbeite Pharmaceutical Co., Ltd.)

1.2.3 Dosage

Tanshinone IIA sodium sulfonate: 15.6mg/kg (high dose), 13.0mg/kg (low dose)

Simvastatin tablets: 1.3mg/kg

2. Modeling, grouping and administration

Fifty mice were randomly divided into blank group, model group, simvastatin group, tanshinone IIA sodium sulfonate high-dose group, and tanshinone IIA sodium sulfonate low-dose group, 10 mice in each group; except the blank group, they were fed with common feed In addition, the mice in the other groups were fed with high-fat diet for 5 weeks; after one week of feeding, except for the blank group and model group, the mice in the other groups were given corresponding drugs by gavage, and the blank group and model group were given the corresponding drugs. An equal volume of distilled water was given to the stomach for 4 consecutive weeks.

3 Observation indicators

After the last administration, the mice were fasted for 12 hours, and the blood was collected by removing the eyeballs, centrifuging, and separating the serum. The levels of TC, TG, HDL-C and LDL-C in serum were detected by kits.

3.5 Statistical processing

表示，多组间比较采用单因素方差分析，两组间采用独立样本T检验方式分析。以P<0.05为差异有统计学意义。SPSS 22.0 software was used for statistical analysis of the obtained data.

One-way analysis of variance was used for comparison among multiple groups, and independent samples T-test was used for analysis between two groups. P<0.05 was considered to be statistically significant.

4. Results and Conclusions

The content of TC, TG and LDL-C in serum of mice fed with high-fat diet increased significantly, while the content of HDL-C decreased significantly (P<0.01);

The serum levels of TC, TG and LDL-C in mice treated with tanshinone IIA sodium sulfonate were significantly decreased, and the HDL-C content was significantly increased (P<0.05 or P<0.01), and the effect was not significantly different from the simvastatin tablet group. (P>0.05).

n＝10，mmol/L)Table 1 Comparison of the levels of TC, TG, HDL-C and LDL-C in the serum of each group of mice (

n=10, mmol/L)

Note: Compared with blank group, @P＜0.05, ^* P＜0.01;

Compared with the model group, ^△ P < 0.05, ^# P < 0.01.

Claims (4)

1. a tanshinone IIA sodium sulfonate tablet, is characterized in that, described tanshinone IIA sodium sulfonate tablet is made up of tablet and coating layer: Described tablet composition is:

The ratio of the lactose, microcrystalline cellulose and sorbitol is 1:2-5:1-3; The coating layer is composed of the following components: Hydroxypropyl methylcellulose 70%-90% Titanium dioxide 10%-30% Magnesium Stearate 1%-2% The total composition of the coating layer is 100%. 2 . The sodium tanshinone IIA sulfonate tablet according to claim 1 , wherein the ratio of lactose, microcrystalline cellulose and sorbitol is 1:3.5:2. 3 . 3. Tanshinone IIA sodium sulfonate tablet as claimed in claim 1, is characterized in that, described coating layer is made up of following components: Hydroxypropyl methylcellulose 75%-80% Titanium dioxide 20%-30% Magnesium Stearate 1%-1.5% The total composition of the coating layer is 100%. 4. A use of the tanshinone IIA sodium sulfonate tablet according to any one of claims 1-3 in the preparation of a medicament for treating hyperlipidemia.

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