Isosorbide mononitrate composition, preparation method and application

Abstract

The invention belongs to the technical field of chronic disease medicine preparations, and particularly relates to an isosorbide mononitrate composition, a preparation method and application. The isosorbide mononitrate composition disclosed by the invention is prepared from isosorbide mononitrate and a hairyvein agrimony extract. According to the invention, the isosorbide mononitrate and the hairyvein agrimony extract are combined for use, so that the effect of synergistically treating the coronary heart disease is achieved, the release speed of the isosorbide mononitrate is delayed, and the long-acting release of the medicine can be maintained.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an isosorbide mononitrate composition, a preparation method and uses thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Coronary heart disease is a chronic disease caused by coronary artery sclerosis and stenosis, which leads to insufficient blood supply to the myocardium, and then causes serious clinical symptoms such as angina pectoris and myocardial infarction. With the development of social economy and changes in lifestyle, coronary heart disease has become one of the main causes of death worldwide. In order to effectively control the symptoms of coronary heart disease and prevent the occurrence of cardiovascular events, drug therapy is currently the most widely used treatment method.

[0004] Isosorbide mononitrate is a drug commonly used for coronary heart disease. It relieves angina pectoris and reduces the burden on the heart by dilating blood vessels and improving the oxygen supply conditions of the heart. As a commonly used vasodilator, isosorbide mononitrate can release nitric oxide, act on vascular smooth muscle, promote vasodilation, and improve coronary blood flow. The Chinese patent with publication number CN 1679536A discloses an isosorbide mononitrate sustained-release tablet for treating coronary heart disease and angina pectoris, which includes isosorbide mononitrate, a sustained-release agent, an adhesive, a filler and a lubricant, and the weight ratio is 100:200-320:50-160:30:1. The preparation process adopts wet granulation, and after the particles are dried and granulated, an appropriate amount of lubricant is added to mix and tablet. The Chinese patent with publication number CN101732276A discloses a double-layer osmotic pump controlled-release tablet of isosorbide mononitrate, which is composed of a double-layer core wrapped with a semipermeable coating film, the double-layer core is composed of a drug-containing layer and a booster layer, and the coating film has a drug-releasing hole on the surface of the drug-containing layer. In the gastrointestinal tract, water enters the double-layer tablet core through the semipermeable membrane. In the drug-containing layer, the drug forms a suspension or solution after meeting water, and the permeation enhancer makes the drug-containing layer solution hypertonic, and there is an osmotic pressure difference between the inside and outside of the membrane, which is conducive to drug pumping out. In the booster layer, the permeation enhancer absorbs water, dissolves and expands to generate pressure, which further pushes the drug solution out of the hole.

[0005] However, as a drug for treating coronary heart disease, although isosorbide mononitrate has certain efficacy, it also has some problems. First, isosorbide mononitrate alone may not achieve the best therapeutic effect. Second, the release rate of isosorbide mononitrate is fast, and it is difficult to maintain the long-term release of the drug, requiring frequent administration, which brings inconvenience to patients.

[0006] In order to solve this problem, combined medication is a common treatment strategy that can bring into play the synergistic effect of different drugs, improve the therapeutic effect and reduce adverse reactions. The combined use of isosorbide mononitrate and agrimony extract may play a synergistic role in the treatment of coronary heart disease, while delaying the release rate of isosorbide mononitrate and achieving long-term release of the drug. Summary of the invention

[0007] In order to overcome the shortcomings of the prior art, the present invention provides a pharmaceutical composition composed of isosorbide mononitrate and herbaceous agrimony extract, aiming to provide a new pharmaceutical preparation for the treatment of coronary heart disease, which can better delay the drug release rate, improve the therapeutic effect, and effectively improve the patient's clinical symptoms and quality of life.

[0008] Specifically, the isosorbide mononitrate composition of the present invention comprises isosorbide mononitrate and agrimony extract in a mass ratio of 10:1-5.

[0009] The preparation method of the herb agrimony extract is as follows:

[0010] (1) Herba Agrimoniae (remove residual roots and impurities, wash, moisten slightly, cut into sections, and dry) is placed in a 6-8 times mass mixed solution of mercaptan acetic acid-ethanol and ultrasonicated for 0.5-1 h, soaked for 3-5 h, and filtered to obtain an extract;

[0011] (2) The filter residue in step (1) is washed with ethanol, 6 to 8 times the weight of 60% to 75% ethanol is added, and the mixture is boiled at 60° C. to 70° C. for 2 to 4 hours, filtered, and the filtrate is collected. The filter residue is added with 5 to 7 times the weight of 75% to 85% ethanol, and the mixture is boiled at 80° C. to 90° C. for 2 to 4 hours, filtered, and a combined filtrate is obtained;

[0012] (3) The extract and the combined filtrate are mixed, and vacuum evaporated in a water bath at 30°C to 85°C until no distillate is produced. The product is filtered and freeze-dried to obtain the product.

[0013] Furthermore, the mass fraction of mercaptan acetic acid in the mercaptan acetic acid-ethanol mixed solution is 2.5% to 5.5%, and the mass fraction of ethanol in the mercaptan acetic acid-ethanol mixed solution is 40% to 60%. The water bath temperature of the vacuum rotary evaporation in the step (4) is initially heated at 30°C, and after no distillate is produced, the temperature is gradually increased by 5°C to 85°C, and the temperature is stopped after no distillate is produced. The freeze drying procedure is: normal pressure -35°C ± 5°C, 5 to 8h, reduced pressure, -5°C ± 5°C, 4 to 6h, reduced pressure, -15°C ± 5°C, 3 to 6h, reduced pressure, 15°C ± 5°C, 8 to 12h.

[0014] The present invention also provides a preparation containing the above-mentioned isosorbide mononitrate composition, wherein the preparation contains pharmaceutically acceptable excipients, including but not limited to fillers, disintegrants, sustained-release materials, lubricants, wetting agents, flavoring agents, coating materials, etc.

[0015] The present invention also provides use of the isosorbide mononitrate composition in preparing a drug for treating coronary heart disease.

[0016] Compared with the prior art, the technical effects of the present invention are:

[0017] The present invention combines the advantages of modern pharmaceutical preparation technology and traditional Chinese medicine to develop a combination preparation of isosorbide mononitrate and agrimony extract, which can not only delay the release rate of isosorbide mononitrate and achieve the long-acting effect of the drug, but also utilize the auxiliary effect of the agrimony extract to enhance the therapeutic effect. This novel composition can not only improve the drug effect persistence of isosorbide mononitrate, but also further improve the comprehensive therapeutic effect of coronary heart disease. The present invention improves the content of agrimonin and agrimonolide in the agrimony extract by optimizing the preparation process of the agrimony extract, especially optimizing the effective component leaching solution system. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 : The contents of agrimonycin and agrimonolide in the agrimony extracts prepared from groups 1 to 6.

[0019] Figure 2 : The cTnI levels in serum of rats in each group after administration.

[0020] Figure 3 : The ratio of TXB2 and 6-Keto-PGF1α in the plasma of rats in each group after administration.

[0021] Figure 4 : The cumulative release rates of the isosorbide mononitrate composition sustained-release tablets of Examples 4 to 6 and the isosorbide mononitrate composition sustained-release tablets of Comparative Example 1. DETAILED DESCRIPTION

[0022] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0023] Example 1 Agrimony Root Extract and Preparation Method

[0024] (1) 50 g of Agrimony stalk was placed in a mixed solution of 50% ethanol with a mass fraction of 3.5% mercaptan acetic acid (7 times its mass) and ultrasonicated for 0.7 h, soaked for 4 h, and filtered to obtain an extract;

[0025] (2) The filter residue in step (1) was washed with ethanol, 7 times the mass of 65% ethanol was added and boiled at 65°C for 3 hours, filtered, and the filtrate was collected. The filter residue was added with 6 times the mass of 80% ethanol and boiled at 85°C for 3 hours, filtered, and a combined filtrate was obtained;

[0026] (3) The extract was mixed with the combined filtrate, and vacuum evaporated in a water bath at 30°C to 85°C until no distillate was produced (the temperature was gradually increased). The product was filtered and freeze-dried at normal pressure, temperature -35°C, for 7 h; pressure <

[0027] 100Pa, temperature -5℃, 5h; pressure <100Pa, temperature -15℃, 5h; pressure <100Pa, temperature 15℃, 10h, and you get it.

[0028] Example 2: Agrimony foetida extract and preparation method

[0029] (1) 50 g of Agrimony granadilla was placed in a mixed solution of 40% ethanol with a mass fraction of 2.5% mercaptan acetic acid (6 times its mass) and ultrasonicated for 0.5 h, soaked for 3 h, and filtered to obtain an extract;

[0030] (2) The filter residue in step (1) was washed with ethanol, 6 times the mass of 60% ethanol was added, and the mixture was boiled at 60°C for 2 h, filtered, and the filtrate was collected. The filter residue was added with 5 times the mass of 75% ethanol, and the mixture was boiled at 80°C for 2 h, filtered, and a combined filtrate was obtained;

[0031] (3) The extract and the combined filtrate are mixed and evaporated under reduced pressure in a water bath at 30°C to 85°C until no distillate is produced (the temperature is gradually increased). The product is filtered and freeze-dried at normal pressure, temperature -40°C, for 5 h; pressure <

[0032] 100Pa, temperature -10℃, 4h; pressure <100Pa, temperature -20℃, 3h; pressure <100Pa, temperature 10℃, 8h, and you'll get it.

[0033] Example 3: Agrimony foetida extract and preparation method

[0034] (1) 50 g of Agrimoniae Herba was placed in a mixed solution of 60% ethanol with a mass fraction of 5.5% mercaptan acetic acid (8 times its mass) and ultrasonicated for 1 h, soaked for 5 h, and filtered to obtain an extract;

[0035] (2) The filter residue in step (1) was washed with ethanol, 8 times the weight of 75% ethanol was added, and the mixture was boiled at 70°C for 4 hours, filtered, and the filtrate was collected. The filter residue was added with 7 times the weight of 85% ethanol, and the mixture was boiled at 90°C for 4 hours, filtered, and a combined filtrate was obtained;

[0036] (3) The extract and the combined filtrate are mixed, and vacuum evaporated in a water bath at 30°C to 85°C until there is no distillate (the temperature is gradually increased). The product is filtered and freeze-dried at normal pressure, temperature -3°C, for 8 h; pressure <100 Pa, temperature 0°C, for 6 h; pressure <100 Pa, temperature -10°C, for 6 h; pressure <100 Pa, temperature 20°C, for 12 h.

[0037] Single factor experiment study

[0038] Using Example 1 as the basic preparation conditions, the vacuum rotary evaporation temperature in step (3) was changed to investigate the residual amounts of mercaptoacetic acid and ethanol in the product before freeze-drying.

[0039] A: The water bath temperature is 30℃~85℃, heating at 5℃ intervals. When there is no distillate, increase by 5℃.

[0040] B: The water bath temperature is 30℃~75℃, heating at 5℃ intervals. When there is no distillate, increase by 5℃.

[0041] C: The water bath temperature is 30℃~65℃, heating at 5℃ intervals. When there is no distillate, increase by 5℃.

[0042] D: The water bath temperature is 30℃~55℃, heating at 5℃ intervals. When there is no distillate, increase by 5℃.

[0043] E: The water bath temperature is kept constant at 85°C.

[0044] Table 1 Residual amounts of mercaptan acetic acid and ethanol

[0045] Ethanol Residue (%) Residual amount of mercaptan acetate (%) A 0 0 B 0 0.22 C 0 0.71 D 0 1.55 E 0 0.19

[0046] Table 1 shows the residual amounts of mercaptan acetic acid and ethanol in the product, indicating that the temperature and temperature control program of the vacuum rotary evaporation have an important influence on the removal of mercaptan acetic acid and ethanol. The program temperature control method prevents mercaptan acetic acid and ethanol from forming azeotropes, avoiding the risk of incomplete removal.

[0047] Using Example 1 as the basic preparation conditions, the solution system of ultrasonic immersion in step (1) was changed, and the effect of the system on the content of the extracted components agrimonycetin and agrimonolide was investigated using high performance liquid chromatography.

[0048] Group 1: 60% ethanol aqueous solution

[0049] Group 2: 3.5% acetic acid mixed with 50% ethanol

[0050] Group 3: 8.5% mercaptoacetic acid mixed with 50% ethanol

[0051] Group 4: 2.5% thiol acetic acid mixed with 20% ethanol

[0052] Group 5: 3.5% citric acid mixed with 50% ethanol

[0053] Group 6: 3.5% thiol acetic acid mixed with 50% ethanol

[0054] Figure 1 The contents of agrimonycin and agrimony lactone in the agrimony extracts prepared from groups 1 to 6. The thiol acetic acid in the system makes it easier for agrimonycin and agrimony lactone to be released and enter the extraction solvent. Its polar part and the polar group of agrimonycin may interact with each other, etc., to increase the solubility of agrimonycin in the mixed solution and improve the extraction efficiency. Ethanol provides a moderately polar environment, which helps to dissolve agrimonycin and agrimony lactone. Ethanol molecules can interact with thiol acetic acid to maintain the stability and solubility of the system, and can also interact with the polar parts of agrimonycin and agrimony lactone to promote their dissolution, thereby increasing the extraction amount of agrimonycin and agrimony lactone.

[0055] The residual amounts of thiol acetic acid and ethanol in the agrimony extracts of Example 1 to Example 3 were all 0, and the contents of agrimonin and agrimonolide in the agrimony extract of Example 1 were 65.43 mg,

[0056] The content of agrimonycin and agrimony lactone in the herb agrimony extract of Example 2 is 61.09 mg and 17.98 mg respectively. The content of agrimonycin and agrimony lactone in the herb agrimony extract of Example 3 is 63.15 mg and 18.06 mg respectively.

[0057] Effect of the combined use of the herb agrimony extract and isosorbide mononitrate in treating coronary heart disease

[0058] The following experimental studies are all conducted on the basis of the safety of the drugs proved by acute toxicity tests and long-term toxicity tests. The dosages used in the experimental studies are all within the safe dosage range.

[0059] SD rats, SPF grade, 180-220 g, experimental animal license number: SYXK(Lu)20180008, were adaptively fed under standard conditions for 1 week before the experiment.

[0060] Several rats were anesthetized, connected to a ventilator, and intubated to expose the heart. The origin of the left anterior descending branch of the coronary artery was visible between the lower edge of the left atrial appendage and the pulmonary artery cone. The left coronary artery was ligated 0.1-0.2 mm below the lower edge of the left atrial appendage. The left coronary artery was observed for several minutes. After ensuring complete hemostasis, the chest cavity was closed layer by layer. After surgery, penicillin sodium (2×10 5U / d, qd) for 3 consecutive days for anti-infection treatment. On the 3rd day after surgery, after anesthesia, cardiac ultrasound examination was performed to evaluate the effect of the coronary artery ligation model. According to the left ventricular myocardial pulsation amplitude, the left ventricular ejection fraction (EF%) was measured, and the animal models that did not meet the standards were eliminated. The rats with successful modeling were divided into experimental group A, experimental group B, experimental group C, model group, control group A, and control group B, with 10 rats in each group. The blank group underwent sham surgery: 10 normal rats were taken, and only the same size of needle suture was taken at the position of the left anterior descending branch of the coronary artery between the lower edge of the left atrial appendage and the pulmonary artery cone without tying a knot, and the rest of the operations were the same as above.

[0061] Experimental group A: isosorbide mononitrate (3.6 mg / kg) + Agrimonia extract of Example 1 (1.8 mg / kg), intragastric administration for 7 days.

[0062] Experimental group B: isosorbide mononitrate (3.6 mg / kg) + Agrimonia extract of Example 1 (0.4 mg / kg), intragastric administration for 7 days.

[0063] Experimental group C: isosorbide mononitrate (3.6 mg / kg) + Agrimonia extract of Example 1 (1.0 mg / kg), intragastric administration for 7 days.

[0064] Control group A: isosorbide mononitrate (3.6 mg / kg), intragastric administration for 7 days.

[0065] Control group B: Agrimoniae extract (1.8 mg / kg) of Example 1 was administered by intragastric gavage for 7 days.

[0066] Rats in the model group and blank group were given equal doses of normal saline for 7 days.

[0067] Expression of Troponin, a Marker of Myocardial Injury in Rats

[0068] Enzyme-linked immunosorbent assay was used to detect the cTnI content in rat serum samples. Troponin cTnI is a highly specific indicator for diagnosing myocardial injury and necrosis. Figure 2 The results show that the cTnI content in the serum of rats in each group after administration indicates that the combined use of isosorbide mononitrate and the herb agrimony extract of the present invention can significantly reduce the cTnI content in the serum of rats. Compared with the model group, the control group A and the control group B, the experimental group A, the experimental group B and the experimental group C are significantly different (P<0.01).

[0069] TXB2 and 6-Keto-PGF in rat plasma 1α Expression

[0070] Detection of TXB2 and 6-Keto-PGF in rat plasma by ELISA 1α , through TXB2, 6-Keto-PGF1α The ratio of the contents determines the severity of coronary heart disease. The higher the ratio, the stronger the tendency of platelet aggregation and vasoconstriction, and the more serious the coronary heart disease. Figure 3 It is the ratio of TXB2 and 6-Keto-PGF1α in the plasma of rats in each group after administration. Compared with the model group, control group A and control group B, there were significant differences among the experimental group A, experimental group B and experimental group C, P < 0.01.

[0071] The experimental data were statistically analyzed using SPSS 22.0 software, and the quantitative data were analyzed using The comparison among multiple groups was performed by one-way analysis of variance, and the comparison between two groups was performed by independent sample T test. P < 0.05 was considered statistically significant.

[0072] Example 4 Isosorbide mononitrate composition sustained-release tablets

[0073] formula:

[0074] Weight(g) Isosorbide mononitrate 10 Example 1 Agrimony Root Extract 3 starch 150 Microcrystalline Cellulose 30 Methylcellulose 40 Sodium alginate 30 Magnesium Stearate 5

[0075] The preparation method is direct tableting.

[0076] Example 5 Isosorbide mononitrate composition sustained-release tablets

[0077] formula:

[0078]

[0079]

[0080] The preparation method is direct tableting.

[0081] Example 6 Isosorbide mononitrate composition sustained-release tablets

[0082] formula:

[0083] Weight(g) Isosorbide mononitrate 10 Example 3 Agrimony Root Extract 5 starch 120 dextrin 20 lactose 60 Methylcellulose 40 Sodium alginate 30 Magnesium Stearate 5

[0084] The preparation method is direct tableting.

[0085] Comparative Example 1 Isosorbide Mononitrate Composition Sustained Release Tablets

[0086] formula:

[0087] Weight(g) Isosorbide mononitrate 10 starch 150 Microcrystalline Cellulose 30 Methylcellulose 40 Sodium alginate 30 Magnesium Stearate 5

[0088] The preparation method is direct tableting.

[0089] Determination of release

[0090] According to the release method under the 2020 edition of the "Chinese Pharmacopoeia" for isosorbide mononitrate sustained-release tablets, the slurry method was adopted, with water as the release medium (volume 900 mL), a rotation speed of 50 rpm, and samples were taken at different times to measure the release.

[0091] Figure 4 The cumulative release rates of the isosorbide mononitrate composition sustained-release tablets of Examples 4 to 6 and the isosorbide mononitrate composition sustained-release tablets of Comparative Example 1 show that the isosorbide mononitrate composition tablets of the present invention have a uniform and slow drug release rate and can maintain drug release for 12 hours.

Claims

1. An isosorbide mononitrate composition, characterized in that The isosorbide mononitrate composition comprises isosorbide mononitrate and agrimony extract in a mass ratio of 10:1-5.

2. The isosorbide mononitrate composition according to claim 1, wherein The preparation method of the herb agrimony extract is as follows: (1) placing the herb in a 6- to 8-fold mass of a mixed solution of mercaptan acetic acid and ethanol, ultrasonicating for 0.5 to 1 hour, soaking for 3 to 5 hours, and filtering to obtain an extract; (2) The filter residue in step (1) is washed with ethanol, 6 to 8 times the weight of 60% to 75% ethanol is added, and the mixture is boiled at 60° C. to 70° C. for 2 to 4 hours, filtered, and the filtrate is collected. The filter residue is added with 5 to 7 times the weight of 75% to 85% ethanol, and the mixture is boiled at 80° C. to 90° C. for 2 to 4 hours, filtered, and a combined filtrate is obtained; (3) The extract and the combined filtrate are mixed, and the mixture is evaporated under reduced pressure in a water bath at 30°C to 85°C until no distillate is produced. The product is filtered and freeze-dried to obtain the product.

3. The isosorbide mononitrate composition according to claim 2, characterized in that The mass fraction of mercaptan acetic acid in the mercaptan acetic acid-ethanol mixed solution is 2.5% to 5.5%, and the mass fraction of ethanol in the mercaptan acetic acid-ethanol mixed solution is 40% to 60%.

4. The isosorbide mononitrate composition according to claim 2, wherein In the step (4), the water bath temperature is gradually increased from 30° C. to 85° C. by heating at 5° C. intervals until no distillate is produced.

5. The isosorbide mononitrate composition according to claim 2, characterized in that The freeze-drying procedure is: normal pressure -35°C±5°C, 5 to 8 h, reduced pressure, -5°C±5°C, 4 to 6 h, reduced pressure, -15°C±5°C, 3 to 6 h, reduced pressure, 15°C±5°C, 8 to 12 h.

6. The isosorbide mononitrate composition according to claim 2, characterized in that The mass fraction of mercaptan acetic acid in the mercaptan acetic acid-ethanol mixed solution is 3.5%.

7. The isosorbide mononitrate composition according to claim 2, characterized in that The mass fraction of ethanol in the mercaptan acetic acid-ethanol mixed solution is 50%.

8. The isosorbide mononitrate composition according to claim 2, characterized in that The freeze-drying procedure is: normal pressure, -35°C, 7h, reduced pressure, -5°C, 5h, reduced pressure, -15°C, 5h, reduced pressure, 15°C, 10h.

9. A preparation containing the isosorbide mononitrate composition according to claim 1, characterized in that: The preparation contains pharmaceutically acceptable excipients.

10. Use of the isosorbide mononitrate composition according to claim 1 in preparing a drug for treating coronary heart disease.

Images