阅读说明：本技术 一种治疗高血压合并冠心病的复方片剂及其制备方法 (Compound tablet for treating hypertension complicated with coronary heart disease and preparation method thereof ) 是由 陈用芳 胡延贵 吴奇财 刘行鹏 樊竞洁 于 2021-01-11 设计创作，主要内容包括：本发明一种治疗高血压合并冠心病的复方片剂,包含阿司匹林片芯、缓释包衣层和苯磺酸左旋氨氯地平薄膜包衣层。本发明将两种药物成分通过合理的制剂工艺,在抑制血小板聚集的同时与其他抗高血压药联合使用,能有效预防高血压、冠心病；表现出协同增效、优势互补的作用。疗效非常显著,副作用小,前景广阔。(The invention relates to a compound tablet for treating hypertension combined with coronary heart disease, which comprises an aspirin tablet core, a slow-release coating layer and a levamlodipine besylate film coating layer. The invention combines the two medicinal components with other antihypertensive drugs while inhibiting platelet aggregation through a reasonable preparation process, and can effectively prevent hypertension and coronary heart disease; shows the effects of synergy and complementary advantages. Has obvious curative effect, small side effect and wide prospect.)

1. A compound tablet for treating hypertension complicated with coronary heart disease comprises a tablet core and a coating layer, and is characterized by comprising an aspirin tablet core, a slow-release coating layer and a levamlodipine besylate film coating layer.

2. The compound tablet for treating hypertension complicated with coronary heart disease according to claim 1, wherein the tablet core comprises the following components in parts by weight:

100-200 parts of aspirin raw material;

2-5 parts of an acidic protective agent;

60-100 parts of a filler;

5-10 parts of a binder;

1.5-3 parts of a lubricant.

3. The compound tablet for treating hypertension complicated with coronary heart disease according to claim 1, wherein the sustained-release coating layer comprises the following components in parts by weight:

10 parts of coating slow-release materials;

2.5-4 parts of a plasticizer;

2.5-4 parts of a pore-foaming agent;

and acetone, wherein the acetone is prepared into a coating liquid with the solid content of 7-10%.

4. The compound tablet for treating hypertension complicated with coronary heart disease according to claim 1, wherein the film coating layer comprises the following components in parts by weight:

2-5 parts of levamlodipine besylate;

8-10 parts of gastric-soluble film coating powder;

and 95% ethanol, wherein the ethanol is prepared into coating liquid with solid content of 8% -10%.

5. The compound tablet for treating hypertension complicated with coronary heart disease according to claim 2, wherein the tablet core contains 120-180 parts of aspirin.

6. The compound tablet for treating hypertension complicated with coronary heart disease according to claim 4, wherein the acidic protective agent is tartaric acid or citric acid, and the amount of the acidic protective agent is 1-3% of aspirin.

7. The compound tablet for treating hypertension complicated with coronary heart disease according to claim 6, wherein the binder is one or more of the following adjuvants: hydroxypropyl methylcellulose, povidone K30 or hydroxypropyl cellulose.

8. The compound tablet for treating hypertension complicated with coronary heart disease according to claim 7, wherein the filler is one or more of the following auxiliary materials: starch, lactose, dextrin, microcrystalline cellulose, pregelatinized starch.

9. The compound tablet of claim 8, wherein the lubricant is magnesium stearate; the coating slow-release material is cellulose acetate; the plasticizer is triethyl citrate, tributyl citrate, pore-forming agent polyvidone and hypromellose; the coating solution used for the film coating layer is prepared by dissolving levamlodipine besylate in 95% ethanol, adding gastric-soluble film coating powder, stirring and dispersing uniformly to obtain the coating solution with the solid content of 8-10%.

10. A method for preparing the compound tablet for treating hypertension complicated with coronary heart disease according to any one of claims 1 to 9: firstly, crushing an aspirin raw material and an acid protective agent and sieving the crushed aspirin raw material and the acid protective agent by a sieve of 80-100 meshes; adding the powder sieve, the filler, the adhesive and the lubricant into a three-dimensional mixer, and mixing for 10-30 min; tabletting after uniformly mixing, wherein a tabletting mold is a shallow concave punch with the diameter of 9mm, and the hardness is controlled to be 5-10 kg during tabletting, the weight range of the tablet is +/-5%, and the friability is less than or equal to 1%; preparing a slow-release coating solution with a solid content of 7-10%, putting tablets into the slow-release coating solution, preheating for 3-5 minutes, adjusting the distance between a spray gun and a spray gun to 10-15 cm, controlling the rotation speed of a liquid feed pump to 20-40 rpm, the rotation speed of a pot body to 3-10 rpm, the air inlet temperature to 30-60 ℃, controlling the tablet temperature to 30-40 ℃ and the atomization pressure to 0.25MPa, after the slow-release coating is finished (the weight is increased by 2-4%) under the condition that the plain tablets are not bonded, drying for 10 minutes, coating with a film coating solution under the same operation condition, and discharging after the film coating is finished.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a compound tablet for treating hypertension complicated with coronary heart disease and a preparation method thereof.

Background

With the continuous improvement of the living standard of human beings and the continuous deterioration of the human environment, the number of cardiovascular patients suffering from hypertension and coronary heart disease is also increasing. According to the relevant data, the number of hypertension patients in China is up to 1.5 hundred million, and the number of hypertension patients increases at the rate of more than 500 million per year. Coronary heart disease is one of the diseases with the highest global mortality, and according to the report of the world health organization in 2011, the number of deaths of coronary heart disease in China is listed second in the world. Therefore, there is a need to develop an excellent drug capable of regulating both blood pressure and coronary heart disease.

Aspirin is still currently the basic drug for antiplatelet prophylactic treatment. The low-dose aspirin can effectively inhibit the production of thromboxane A2, so that platelet aggregation is resisted, and the risk of thrombus formation caused by platelet aggregation caused by plaque rupture or other reasons is reduced. Aspirin has a definite anti-platelet effect, the drug effect of aspirin can last the whole platelet life cycle, the aspirin is the most economical anti-platelet drug, in the aspect of secondary prevention of the existing cardiovascular disease patients and the prevention of secondary recurrence of the cardiovascular disease, aspirin is one of the first-choice drug and basic drug, in the aspect of primary cardiovascular prevention of the cardiovascular disease high-risk patients, the application of aspirin needs to perform more evaluations and patient education, fully understand the possibility of bleeding risk caused by aspirin, and evaluate the balance between the benefit of primary prevention and the bleeding risk when aspirin is taken. Briefly, secondary prevention aspirin is usually taken for a long period of time, while primary prevention should be more conservative, taking into account the risks associated with administration.

The levamlodipine besylate is a novel antihypertensive drug obtained by separating a levorotatory isomer with drug effect on the basis of an antihypertensive drug amlodipine besylate, compared with a common amlodipine tablet, the half-life period of the levamlodipine besylate is longer and can be as long as 50 hours (about 35 hours of the common amlodipine), so that the antihypertensive effect is more durable, the drug dosage is also halved (the antihypertensive effect of 2.5mg daily dose of the levamlodipine is equivalent to 5mg daily dose of the common amlodipine), the occurrence rate of side effects of the drug and the drug safety are also improved to a certain extent, and the levamlodipine besylate is a commonly used antihypertensive drug for hypertension patients. The levamlodipine is a good antihypertensive drug for treating the initial treatment of hypertension, senile hypertension, salt-sensitive hypertension and combined medication of hypertension, patients with hypertension complicated with coronary heart disease and the condition of hypertension complicated with carotid arteriosclerosis. Compared with the amlodipine besylate, the levamlodipine besylate eliminates the dextroamlodipine besylate without bioactivity, has better treatment effect and less adverse reaction.

Hypertension is commonly associated with coronary heart disease, both of which are considered to be major risk factors for developing and causing cardiovascular diseases, so that for hypertensive patients, attention is paid to control of coronary heart disease while treating hypertension.

Therefore, the invention is especially provided.

Disclosure of Invention

In order to solve the problems, the invention provides a compound tablet which has small toxic and side effects and high safety and is used for treating hypertension complicated with coronary heart disease and a preparation method thereof. The combined application of the levamlodipine and the aspirin effectively solves the problem, and the levamlodipine and the aspirin can play an additive and synergistic effect to effectively control the conditions of patients with hypertension and coronary heart disease. The compound tablet comprises an aspirin tablet core, a slow-release coating layer and a levamlodipine besylate film coating layer.

Preferably, the tablet core comprises, in parts by weight:

100-200 parts of aspirin raw material;

2-5 parts of an acidic protective agent;

60-100 parts of a filler;

5-10 parts of a binder;

1.5-3 parts of a lubricant.

In any of the above embodiments, preferably, the sustained-release coating layer comprises, in parts by weight:

10 parts of coating slow-release materials;

2.5-4 parts of a plasticizer;

2.5-4 parts of a pore-foaming agent;

and acetone, wherein the acetone is prepared into a coating liquid with the solid content of 7-10%.

In any of the above embodiments, preferably, the film coating layer comprises, in parts by weight:

2-5 parts of levamlodipine besylate;

8-10 parts of gastric-soluble film coating powder;

and 95% ethanol, wherein the ethanol is prepared into coating liquid with solid content of 8% -10%.

In any of the above schemes, preferably, the tablet core contains 120-180 parts of aspirin.

In any of the above schemes, preferably, the acidic protective agent is tartaric acid or citric acid, and the amount of the acidic protective agent is 1% -3% of aspirin.

In any of the above embodiments, preferably, the adhesive is one or more of the following auxiliary materials: hydroxypropyl methylcellulose, povidone K30 or hydroxypropyl cellulose.

In any of the above embodiments, preferably, the filler is one or more of the following adjuvants: starch, lactose, dextrin, microcrystalline cellulose, pregelatinized starch.

Preferably in any of the above embodiments, the lubricant is magnesium stearate; the preferable dosage is 0.5-1% of the tablet core weight.

In any of the above embodiments, preferably, the coated sustained-release material is cellulose acetate; the plasticizer is triethyl citrate, tributyl citrate, pore-forming agent polyvidone, and hypromellose.

Preferably, in any scheme, the coating solution used for the film coating layer is prepared by dissolving levamlodipine besylate in 95% ethanol, adding gastric-soluble film coating powder, stirring and dispersing uniformly to obtain the coating solution with the solid content of 8-10%.

The invention also provides a preparation method of the compound tablet for treating hypertension complicated with coronary heart disease, which comprises the following steps: firstly, crushing an aspirin raw material and an acid protective agent and sieving the crushed aspirin raw material and the acid protective agent by a sieve of 80-100 meshes; adding the powder sieve, the filler, the adhesive and the lubricant into a three-dimensional mixer, and mixing for 10-30 min; tabletting after uniformly mixing, wherein a tabletting mold is a shallow concave punch with the diameter of 9mm, and the hardness is controlled to be 5-10 kg during tabletting, the weight range of the tablet is +/-5%, and the friability is less than or equal to 1%; preparing a slow-release coating solution with a solid content of 7-10%, putting tablets into the slow-release coating solution, preheating for 3-5 minutes, adjusting the distance between a spray gun and a spray gun to 10-15 cm, controlling the rotation speed of a liquid feed pump to 20-40 rpm, the rotation speed of a pot body to 3-10 rpm, the air inlet temperature to 30-60 ℃, controlling the tablet temperature to 30-40 ℃ and the atomization pressure to 0.25MPa, after the slow-release coating is finished (the weight is increased by 2-4%) under the condition that the plain tablets are not bonded, drying for 10 minutes, coating with a film coating solution under the same operation condition, and discharging after the film coating is finished.

Compared with the prior art, the invention has the beneficial effects that: the invention adopts the membrane-controlled slow release technology to ensure that aspirin can take effect, reduce blood concentration and reduce adverse reaction rate. The aspirin release is less than or equal to 15% in 1 hour, less than or equal to 60% in 6 hours and more than or equal to 90% in 18 hours. The levamlodipine besylate is selected for reducing blood pressure, and compared with the amlodipine besylate, the levamlodipine besylate without bioactivity is removed, so that the therapeutic effect is better, the drug dosage is halved, and the adverse reaction is less. The invention combines the two medicinal components with other antihypertensive drugs while inhibiting platelet aggregation through a reasonable preparation process, and can effectively prevent hypertension and coronary heart disease; shows the effects of synergy and complementary advantages. Has obvious curative effect, small side effect and wide prospect.

Drawings

FIG. 1 is a graph showing the results of a release rate measurement curve of aspirin in examples 1 to 3 of the present invention.

Detailed Description

Example 1

A compound tablet for treating hypertension complicated with coronary heart disease, the weight portion ratio of each component is shown in Table 1.

TABLE 1

The preparation method comprises the following steps:

firstly, crushing an aspirin raw material and tartaric acid and sieving the mixture by a sieve of 80-100 meshes; adding the powder sieve, pregelatinized starch, hydroxypropyl methylcellulose and magnesium stearate into a three-dimensional mixer, and mixing for 10-30 min; tabletting after uniformly mixing, wherein a tabletting mold is a shallow concave punch with the diameter of 9mm, and the hardness is controlled to be 5-10 kg during tabletting, the weight range of the tablet is +/-5%, and the friability is less than or equal to 1%; preparing a slow-release coating solution with a solid content of 7-10%, putting tablets into the slow-release coating solution, preheating for 3-5 minutes, adjusting the distance between a spray gun and a spray gun to 10-15 cm, controlling the rotation speed of a liquid feed pump to 20-40 rpm, the rotation speed of a pot body to 3-10 rpm, the air inlet temperature to 30-60 ℃, controlling the tablet temperature to 30-40 ℃ and the atomization pressure to 0.25MPa, after the slow-release coating is finished (the weight is increased by 2-4%) under the condition that the plain tablets are not bonded, drying for 10 minutes, coating with a film coating solution under the same operation condition, and discharging after the film coating is finished.

Example 2

A compound tablet for treating hypertension complicated with coronary heart disease, the weight portion ratio of each component is shown in Table 2.

TABLE 2

The preparation method comprises the following steps:

firstly, crushing an aspirin raw material and tartaric acid and sieving the mixture by a sieve of 80-100 meshes; adding the powder sieve, lactose, povidone K30 and magnesium stearate into a three-dimensional mixer, and mixing for 10-30 min; tabletting after uniformly mixing, wherein a tabletting mold is a shallow concave punch with the diameter of 9mm, and the hardness is controlled to be 5-10 kg during tabletting, the weight range of the tablet is +/-5%, and the friability is less than or equal to 1%;

preparing a slow-release coating solution with a solid content of 7-10%, putting tablets into the slow-release coating solution, preheating for 3-5 minutes, adjusting the distance between a spray gun and a spray gun to 10-15 cm, controlling the rotation speed of a liquid feed pump to 20-40 rpm, the rotation speed of a pot body to 3-10 rpm, the air inlet temperature to 30-60 ℃, controlling the tablet temperature to 30-40 ℃ and the atomization pressure to 0.25MPa, after the slow-release coating is finished (the weight is increased by 2-4%) under the condition that the plain tablets are not bonded, drying for 10 minutes, coating with a film coating solution under the same operation condition, and discharging after the film coating is finished.

Example 3

A compound tablet for treating hypertension complicated with coronary heart disease, the weight portion ratio of each component is shown in Table 3.

TABLE 3

The preparation method comprises the following steps:

firstly, crushing an aspirin raw material and citric acid and sieving the mixture by a sieve of 80-100 meshes; adding the powder sieve, microcrystalline cellulose, hydroxypropyl methylcellulose and magnesium stearate into a three-dimensional mixer, and mixing for 10-30 min; tabletting after uniformly mixing, wherein a tabletting mold is a shallow concave punch with the diameter of 9mm, and the hardness is controlled to be 5-10 kg during tabletting, the weight range of the tablet is +/-5%, and the friability is less than or equal to 1%;

preparing a slow-release coating solution with a solid content of 7-10%, putting tablets into the slow-release coating solution, preheating for 3-5 minutes, adjusting the distance between a spray gun and a spray gun to 10-15 cm, controlling the rotation speed of a liquid feed pump to 20-40 rpm, the rotation speed of a pot body to 3-10 rpm, the air inlet temperature to 30-60 ℃, controlling the tablet temperature to 30-40 ℃ and the atomization pressure to 0.25MPa, after the slow-release coating is finished (the weight is increased by 2-4%) under the condition that the plain tablets are not bonded, drying for 10 minutes, coating with a film coating solution under the same operation condition, and discharging after the film coating is finished.

Example 4

The test curve of aspirin release in examples 1 to 3 was determined by the second method of "Chinese pharmacopoeia", wherein 900mL of aspirin release medium, 100rpm of rotation speed, 37. + -. 0.5 ℃ of temperature, pH 6.8 of phosphate buffer was used as the medium for 1, 3, 6, 9, 12, 15, 18 and 21 hours, 5mL of the treated solution was used as a test solution, and ultraviolet absorbance was measured at 265 nm.

Table 4 release data of aspirin for each example

Example 5

Clinical trial

Selecting 102 patients suffering from hypertension and coronary atherosclerosis simultaneously, averagely dividing the patients into two groups with the average age of 62.2 +/-8.5, wherein each group contains 51 people, and the control group is given with 2.5 mg/day of levamlodipine besylate tablet (Shihudada), 10 mg/time of isosorbide dinitrate tablet (Xiaoxintong tablet) and 3 times/day; study groups received the pharmaceutical composition of example 1, 1 tablet per day; the administration is continued for 3 months.

Observation indexes are as follows: changes in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Total Cholesterol (TC), Triglycerides (TG), Left Ventricular Ejection Fraction (LVEF), plasma viscosity and platelet aggregation rate before and after 3 months of treatment were observed in both groups of patients.

Evaluation indexes are as follows: the effect is shown: SBP/DBP is reduced to below 140/90mmHg, Pulse Pressure (PP) is less than or equal to 50mmHg, the electrocardiogram is recovered to normal when resting, and the double-step ladder exercise test is converted from positive to negative; the method has the following advantages: DBP is reduced by less than 20mmHg or SBP is reduced by less than 30mmHg, PP is reduced by less than 50mmHg and 100mmHg, and ST section is reduced by more than 0.05 mV after treatment in an electrocardiogram or double two-step exercise test at rest but is not normal; and (4) invalidation: the blood pressure drop does not meet the above standard, and the electrocardiogram or exercise test is basically the same as before the treatment.

The total effective rate is significant efficiency + effective rate.

TABLE 5 comparison of blood pressure and blood lipid before and after treatment

Comparing blood pressure and blood fat before and after two groups of treatments: before treatment, SBP, DBP, TC and TG levels in the two groups were comparable, and the differences were not statistically significant. After 3 months of treatment, the SBP, DBP, TC and TG levels in the two groups were reduced to different degrees, but the comparison difference of the data after the two groups of treatment has no statistical significance.

TABLE 6 comparison of plasma viscosity, platelet aggregation Rate and LVEF before and after treatment in two groups

Plasma viscosity, platelet aggregation rate and LVEF comparison before and after treatment in both groups: before treatment, the plasma viscosity, platelet aggregation rate and LVEF of the two groups are equivalent, and the difference has no statistical significance. After 3 months of treatment, the plasma viscosity and the platelet aggregation rate of the two groups are reduced to different degrees compared with those before treatment, the plasma viscosity and the platelet aggregation rate of the research group are obviously reduced to a greater extent than those of the control group compared with those before treatment, the LVEF of the two groups is obviously increased after 3 months of treatment, and the LVEF level of the research group is obviously higher than that of the control group.

TABLE 7 comparison of Total effectiveness of two treatments

Comparison of overall efficacy of two groups of clinical treatments: after 3 months of treatment, the total effective rate of the study group is 92.1%, the total effective rate of the control group is 74.5%, and the total effective rate of the study group is obviously higher than that of the control group; the aspirin and the levamlodipine besylate have synergistic effect, and the medicinal composition can be used for the combined treatment of the hypertension and the coronary heart disease.

The inventive concept is explained in detail herein using specific examples, which are given only to aid in understanding the core concepts of the invention. It should be understood that any obvious modifications, equivalents and other improvements made by those skilled in the art without departing from the spirit of the present invention are included in the scope of the present invention.