CN112999216B

CN112999216B - A pharmaceutical composition containing tylosin for treating diabetic cardiomyopathy

Info

Publication number: CN112999216B
Application number: CN202110230384.6A
Authority: CN
Inventors: 高悦译; 刘恩桂; 张倩; 卢江
Original assignee: Guangzhou Lixin Pharmaceuticals Co ltd
Current assignee: Guangzhou Lixin Pharmaceuticals Co ltd
Priority date: 2021-03-02
Filing date: 2021-03-02
Publication date: 2022-05-06
Anticipated expiration: 2041-03-02
Also published as: CN112999216A

Abstract

The invention relates to the technical field of medicines, and particularly discloses a pharmaceutical composition containing tylosin and used for treating diabetic cardiomyopathy. The pharmaceutical composition comprises the tylosin and a statin lipid-regulating drug, wherein the statin lipid-regulating drug comprises one of lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin and pitavastatin. The synergistic effect of the tylosin and the statins effectively controls the blood sugar concentration of a diabetic patient, has a certain effect on treating the complication myocardial dysfunction caused by diabetes, has small toxic and side effects, and is safer and more effective in use.

Description

A pharmaceutical composition containing tylosin for treating diabetic cardiomyopathy

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition containing tylosin and used for treating diabetic cardiomyopathy.

Background

With the rapid development of social economy, the living standard of people is continuously improved, the prevalence rate of diabetes of adults in China is remarkably increased, and the prevalence rate is increased from 0.67% in 1980 to 10.4% in 2013. The 8 th edition of global Diabetes map data issued by International Diabetes Federation (IDF) in 2017 shows that the prevalence rate of Diabetes in China in 2017 is 10.9%, the number of diabetics reaches 1.14 hundred million, accounts for more than 25% of the total number of adult diabetics in the world, and is located in the world first, and the data is still continuously increasing, and is predicted to increase to 1.2 hundred million by 2045 years. Therefore, the prevention and treatment of diabetes is particularly important. At present, the treatment strategy of diabetes is a comprehensive management mode, including blood sugar reduction, blood pressure reduction, blood fat regulation, platelet resistance, weight control, life style improvement and the like. Despite the adoption of perfect comprehensive management, some patients still have poor blood sugar control effect. In recent years, diabetes has become one of the serious metabolic diseases in China. Complications caused by diabetes are important factors of death and threaten the life and health of human beings. Diabetes is a metabolic disease affecting the health of people worldwide, and the number of diabetic patients is increased to 5.5 hundred million by 2030 according to the international diabetes union.

There are numerous complications of diabetes, such as diabetic foot, diabetic nephropathy, fibrosis due to diabetes, and the like. Diabetic Cardiomyopathy (DCM), which is one of the important complications of Diabetes Mellitus (DM), is recognized as a metabolic disorder of the heart muscle, microangiopathy, fibrosis/hypertrophy of the heart muscle, and finally damage to the cardiac function, resulting in heart failure, functionally manifested as diastolic compliance and cardiac contractility, which are one of the main causes of death from DM, secondary to hyperglycemia and myocardial lipotoxicity. A large proportion of diabetic patients suffer from diabetic cardiomyopathy, and this phenomenon occurs in both type 1 and type 2 diabetic patients. The pathogenesis of DCM is still unknown at present, and may be related to factors such as sugar and lipid metabolism disorder, myocardial apoptosis caused by oxidative stress, inflammatory reaction, endothelial function damage and the like caused by insulin secretion abnormality, myocardial fibrosis, disorder of long-chain non-coding RNA (lncRNA), micro RNA (MicroRNA), immunological change and the like. Effective blood sugar control is still the basic treatment measure of DCM, and risk factors such as blood fat, blood pressure and the like are controlled, and symptomatic treatment for preventing and treating heart failure is provided to protect cardiac muscle, delay the development of DCM and improve the prognosis of patients, so that specific treatment medicines are still lacked at present.

It has been found that the drug telagliflozin studied using dapagliflozin as a lead compound has a smaller IC in inhibition of SGLT2 than dapagliflozin₅₀The dapagliflozin is a range which has a drug effect longer than that of dapagliflozin and is at least 6-18 mg/kg in vivo by combining UGE data analysis of ratsSGLT2 inhibitors that are more potent than dapagliflozin in the peri-domain. Patent document CN111588713A discloses a pharmaceutical composition for treating diabetes, which comprises tylosin, metformin and additives, can effectively treat type 2 diabetes, has good patient compliance, and can prevent the recurrence of diabetes; patent document CN111494358A discloses a drug for treating and preventing diabetic nephropathy, which comprises tylosin and DPP24 inhibitor, and can significantly reduce the content and expression level of blood urea nitrogen, blood creatinine and the like through the action between drugs, significantly increase the expression level of cloroxol protein, and achieve the effect of effectively treating and preventing diabetic nephropathy.

At present, most of the medicines for treating the diabetic cardiomyopathy are hypoglycemic medicines such as metformin, thiazolidinediones, namely insulin sensitizers, natural glucagon-like peptide-1, dipeptidyl peptidase-4 and the like, and the medicines have certain toxic and side effects and use limitation when being clinically used for treating the diabetic cardiomyopathy, so that continuous research finds that a medicine capable of effectively treating the diabetic cardiomyopathy is very urgent, and meanwhile, the existing technology for treating the diabetic cardiomyopathy by the tylosin is not found through retrieval.

Disclosure of Invention

The invention aims to provide a drug composition containing tylosin and used for treating diabetic cardiomyopathy, which can effectively relieve the problems of myocardial metabolic disorder, microangiopathy, myocardial fibrosis/hypertrophy and the like caused by hyperglycemia and myocardial lipotoxicity caused by diabetic cardiomyopathy, and can effectively control the blood glucose and blood lipid concentration level of a diabetic patient to achieve the effect of treating diabetic cardiomyopathy.

The invention realizes the aim through the following technical scheme: a pharmaceutical composition containing tylosin for treating diabetic cardiomyopathy comprises tylosin and statin lipid-regulating drugs.

Preferably, the statin lipid-regulating drug comprises one of lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin and pitavastatin.

Preferably, the statin lipid-regulating drug is pravastatin.

Preferably, the weight part ratio of the tylosin to the statin lipid-regulating drugs is (1-3): (2-5).

Preferably, the pharmaceutical composition further comprises a pharmaceutical adjuvant, and further, the pharmaceutical adjuvant comprises a binder, a filler, a disintegrant and a lubricant.

Preferably, the weight part ratio of the main drug tylosin and statin drug composition to the pharmaceutical excipients is 1: (6-8).

Preferably, the pharmaceutical composition is an oral formulation.

Preferably, the oral formulation includes tablets, granules and capsules.

Preferably, the pharmaceutical composition is applied to the preparation of a medicament for treating diabetic cardiomyopathy.

The invention combines the tylagliflozin and the pravastatin, tests on various serum indexes and myocardial functions of a type 2 DCM rat show that the synergistic effect between the tylagliflozin and the pravastatin can effectively protect the cardiac function, improve the glycolipid metabolism of an organism, regulate the TC and TG disorders of the serum of the rat, reduce the toxic and side effects generated by the medicine and protect the myocardial tissue of the diabetic rat, and meanwhile, the invention enhances the convenience and the safety of the medicine taking of the diabetic myocardial disease patient by common oral preparation formulations such as granules, tablets and capsules.

Therefore, compared with the prior art, the invention has the following beneficial effects:

(1) the invention provides a new application of tylosin in the field of medicines, namely the combination of the tylosin and a statin lipid-regulating medicine can be used as a medicine for treating diabetic cardiomyopathy, and the effects of preventing and improving myocardial fibrosis and improving left ventricular hypertrophy are achieved.

(2) The invention obviously enhances the treatment effect of the medicament on diabetes and diabetic complication diabetic cardiomyopathy through the synergistic effect generated between the tylosin and the statins.

(3) The pharmaceutical composition has lower toxic and side effects of the medicine, the single medicine pravastatin has the defects of short half-life period, poor medicine treatment capability and the like in use, and meanwhile, the dapagliflozin has certain gastrointestinal toxicity in practical application.

Detailed Description

The present invention will be further described below by way of specific embodiments, but the present invention is not limited to only the following examples. It will be apparent to those skilled in the art that the invention can be modified and replaced with other components having the same effects without departing from the spirit and scope of the invention, and all such modifications and substitutions are deemed to be within the scope of the invention.

Example 1 pharmaceutical composition for treating diabetic cardiomyopathy of the present invention

Is prepared by mixing 10g of tylosin and 15g of pravastatin.

Example 2 pharmaceutical composition for treating diabetic cardiomyopathy of the present invention

Is prepared by mixing 5g of tylosin and 20g of pravastatin.

Example 3 pharmaceutical compositions of the invention for the treatment of diabetic cardiomyopathy

Is prepared by mixing 7g of tylosin and 18g of pravastatin.

Example 4 tablets containing the pharmaceutical composition for the treatment of diabetic cardiomyopathy of the present invention

The preparation method comprises the following steps: taking the tylosin and pravastatin according to the formula amount, taking hydroxypropyl cellulose as a bonding agent, microcrystalline cellulose as a filling agent, low-substituted hydroxypropyl cellulose as a disintegrating agent and magnesium stearate as a lubricating agent, uniformly mixing, and tabletting according to the conventional process of tablets to obtain the tablet.

Example 5 tablets containing the pharmaceutical composition for the treatment of diabetic cardiomyopathy of the present invention

The preparation method comprises the following steps: taking the tylosin and pravastatin according to the formula amount, uniformly mixing hydroxypropyl cellulose serving as a bonding agent, microcrystalline cellulose serving as a filling agent, low-substituted hydroxypropyl cellulose serving as a disintegrating agent and magnesium stearate serving as a lubricating agent, and tabletting according to the conventional process of tablets to obtain the tablet.

Example 6 tablets containing the pharmaceutical composition for the treatment of diabetic cardiomyopathy of the present invention

Test example I Effect of pharmaceutical composition containing tylosin on myocardial contractile function of type 2 DCM rats

First, experimental sample

1.1 preparation of animal models

Preparing 90 healthy and clean male SD rats, feeding 80 rats with high-sugar and high-fat diet, carrying out intraperitoneal injection of streptozotocin (STZ,15mg/kg and QW multiplied by 4) to establish a model of induction type 2 DCM rats, detecting cardiac function by using an echocardiogram during screening, and detecting blood glucose concentration by using blood glucose test paper, wherein the establishment of the model of type 2 DCM is considered to be successful if the blood glucose is more than or equal to 16.7mmol/L and the-dp/dtmax is less than or equal to 5250 mm Hg/s. Rats in the placebo group were fed on their normal diet and gazed with a certain amount of physiological saline.

1.2 the successfully molded rats are randomly divided into the following groups:

model group: perfusing normal saline with the same volume as that of the blank control group;

captopril intervention group: performing intragastric administration with 3.91 mg/kg-1/d-1 captopril solution;

example 1 group: performing intragastric administration by using a solution of 1.04 mg.kg-1. d-1 tylosin and 1.56 mg.kg-1. d-1 pravastatin;

example 2 group: performing intragastric administration by using 0.52 mg.kg-1.d-1 tylosin and 2.08 mg.kg-1.d-1 pravastatin solution;

example 3 group: performing intragastric administration by using 0.74 mg.kg-1.d-1 tylosin and 1.86 mg.kg-1.d-1 pravastatin solution;

comparative example 1 group: performing intragastric administration with 2.60 mg/kg-1/d-1 tylosin solution;

comparative example 2 group: performing intragastric administration with 2.60 mg/kg-1/d-1 pravastatin solution;

comparative example 3 group: performing intragastric administration by using a solution of 1.04 mg.kg-1. d-1 dapagliflozin and 1.56 mg.kg-1. d-1 pravastatin;

each group was fed with 10 animals, a placebo group on a normal diet, and the other groups were fed with a high-sugar, high-fat diet during the administration period.

Second, Experimental methods

2.1 testing of serum and myocardial different indices of various groups of rats

And (4) taking blood from tail veins at the end of 15 weeks, and detecting the fasting blood glucose of each group by adopting blood glucose test paper. Collecting abdominal aorta blood, centrifuging at 3000 r/min for 10min to separate serum, and detecting Ang II level of serum by enzyme-linked immunosorbent assay (ELISA), wherein the specific method is described with reference to kit. Pentobarbital sodium 1% was injected intraperitoneally at 20mg/kg, cannulated into the left ventricle via the right carotid artery, and the maximum rate of rise/fall of left ventricular pressure (LV ± dp/dtmax) was determined during isovolumic relaxation/contraction, and Left Ventricular Ejection Fraction (LVEF) was determined by echocardiography. Rat myocardial tissue was removed rapidly and washed with cold isotonic saline, blotted with filter paper, and weighed wet (HW). Taking each group of myocardial tissue sections, staining by a TUNEL apoptosis staining method, randomly selecting 5 visual fields for each stained section under an optical microscope with the power of 400 times, recording the number of all myocardial cells and apoptotic cells, and calculating an Apoptosis Index (AI) of the myocardial cells.

The method comprises the steps of extracting eyeball blood of each group of rats from a model 2 DCM rat, centrifuging at 4 ℃ by a high-speed refrigerated centrifuge to obtain serum, and detecting the contents of Total Cholesterol (TC), Triglyceride (TG), Lactate Dehydrogenase (LDH), Creatine Kinase (CK), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in the serum of each group of rats by a biochemical method.

2.2 statistical analysis

The experimental data are statistically analyzed by SPSS 22.0 software, the measurement data are expressed by mean +/-standard deviation, t test is adopted for data comparison before and after intervention, one-factor variance analysis is adopted for data comparison between groups, and P <0.05 has statistical significance for difference.

Third, experimental results

3.1 comparison of blood glucose and serum Ang II levels in rats of each group

The blood sugar level and the serum Ang II level of the model group rats are higher than those of the blank control group, and the difference has statistical significance (P < 0.05); in examples 1-3, the blood sugar level and the serum Ang II level of rats are lower than those of the model group, and the difference has statistical significance (P < 0.05); the serum AngII level of rats in the captopril intervention group is lower than that of the rats in the model group, and the difference has statistical significance (P < 0.05); the blood sugar of rats in the comparative examples 1-3 groups is lower than that of the model group, the level of serum Ang II is lower than that of the model group, the difference has statistical significance (P is less than 0.05), and the experimental data are shown in table 1.

TABLE 1 comparison of blood glucose, serum Ang II levels in rats of various groups

Note: p <0.05 compared to model group.

The data in table 1 show that the blood sugar and serum Ang ii levels of DCM rats in examples 1 to 3 of the present invention are lower than those in the model group and the captopril intervention group, which proves that the present invention can effectively reduce the symptoms of hyperglycemia and hyperlipidemia caused by diabetic cardiomyopathy, and the data show that the blood sugar content and serum Ang ii levels of the rats in examples 1 to 3 of the present invention are lower than those in comparative examples 1 to 3, which shows that the combined use of taxol and pravastatin can effectively reduce the symptoms of hyperglycemia and hyperlipidemia caused by diabetic cardiomyopathy.

3.2 rat serum index detection

The serum index detection results are shown in tables 2-4.

TABLE 2 comparison of TC and TG contents in rats of each group

Note: p <0.05 compared to model group.

TABLE 3 comparison of HDL and LDL contents in rats of each group

Note: p <0.05 compared to model group.

TABLE 4 comparison of LDH and CK content in rats of each group

Note: p <0.05 compared to model group.

As can be seen from the data in tables 2 to 4, the groups of examples 1 to 3 of the present invention can significantly reduce the content levels of Total Cholesterol (TC), Lactate Dehydrogenase (LDH), Creatine Kinase (CK), High Density Lipoprotein (HDL), and Low Density Lipoprotein (LDL) in the serum of rats with type 2 DCM, and are all lower than those of captopril pretreatment group, comparative examples 1 to 3 and model group. Compared with the data of the examples 1-3 groups and the comparative examples 1-3 groups, the synergistic effect between the tylosin and pravastatin can be further proved, and the synergistic effect has the effects of remarkably improving the glycolipid metabolism of rats with type 2 DCM, regulating the serum TC and TG disorder of the rats and protecting the heart, and finally achieves the effect of treating the diabetic cardiomyopathy.

3.3 comparison of different indices of myocardium in rats of various groups

The model group rat HW and AI are higher than the control group, LV + -dp/dtmax and LVEF are lower than the blank control group, and the difference has statistical significance (P < 0.05); the HW and AI of rats in the groups 1 to 3 of examples and the groups 1 to 3 of comparative examples are lower than those in the model group, LV +/-dp/dtmax and LVEF are higher than those in the model group, and the difference has statistical significance (P < 0.05); the rat HW of the captopril intervention group is lower than that of the model group, LV +/-dp/dtmax and LVEF are both higher than those of the model group, and the difference has statistical significance (P < 0.05); compared with the model group, the differences of the rats AI in the captopril intervention group are not statistically significant (P >0.05), and the experimental data are shown in Table 2.

TABLE 5 comparison of different indices of myocardium in rats of various groups

Note: p <0.05 compared to model group.

As can be seen from the data in Table 5, the groups 1 to 3 of the invention can significantly increase the maximum rate of the rise/fall of the left ventricular pressure in the isovolumetric relaxation/contraction period of the type 2 DCM rat, and both are higher than the data level in the captopril intervention group, and the wet weight and the myocardial apoptosis index of the rat myocardial tissue rapidly taken out of the groups 1 to 3 are lower than those of the model group and the groups 1 to 3 of the comparative example, so that the groups 1 to 3 of the invention have significant protective effect on the heart function of the type 2 DCM rat. In addition, it can be obtained from the left ventricular ejection fraction in table 2 that the pharmaceutical composition of tylosin and pravastatin of the present invention does not affect the cardiac function of type 2 DCM rats and simultaneously plays a role in protecting the cardiac function, and the data in examples 1-3 and comparative examples 1-3 demonstrate that the synergistic effect between tylosin and pravastatin of the present invention can significantly improve the therapeutic effect on diabetic cardiomyopathy, and simultaneously has little toxic and side effects on human bodies and improves the safety of patients taking drugs.

The tests can show that the synergistic effect of the tylosin and pravastatin in the technology can protect the heart, improve the glycolipid metabolism, regulate the serum TC and TG disorder of rats, reduce the toxic and side effect of the drug and protect the myocardial tissue of the diabetic rats, and the convenience and the safety of the drug administration of the diabetic myocardial patients are enhanced by the common oral dosage forms of granules, tablets and capsules.

The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.

Claims

1. A pharmaceutical composition containing tylosin for treating diabetic cardiomyopathy is characterized in that the active drug consists of tylosin and statin lipid-regulating drugs;

the statin lipid-regulating drug is pravastatin;

the weight part ratio of the tylosin to the statin lipid-regulating medicine is (1-3): (2-5).

2. The pharmaceutical composition of claim 1, further comprising a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a binder, a filler, a disintegrant, and a lubricant.

3. The pharmaceutical composition of claim 2, wherein the weight part ratio of the active drug to the pharmaceutical excipients is 1: (6-8).

4. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is an oral formulation.

5. The pharmaceutical composition of claim 4, wherein the oral formulation is selected from the group consisting of tablets, granules, and capsules.

6. Use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a medicament for treating diabetic cardiomyopathy.