Pharmaceutical composition for preventing and treating pulmonary arterial hypertension and preparation method and application thereof

Abstract

The invention relates to the technical field of biological medicine, in particular to a pharmaceutical composition for preventing and treating pulmonary arterial hypertension and a preparation method and application thereof. The invention provides a pharmaceutical composition for preventing and treating pulmonary arterial hypertension. The pharmaceutical composition is prepared from the following components: saltinib, azilsartan, baicalein, sinomenine and tanshinol. Different components are combined to treat pulmonary arterial hypertension, a good treatment effect is achieved, the composition can effectively reduce the pulmonary arterial pressure of an animal model and can also remarkably reduce systemic circulation pressure, the treatment effect of the composition is obviously superior to that of drugs in the prior art, and the composition has wide application prospects.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to a pharmaceutical composition for preventing and treating pulmonary hypertension, and a preparation method and application thereof. Background Art

[0002] Pulmonary hypertension (PH) is a serious circulatory disease, which is defined as changes in pulmonary vascular structure and / or function caused by a variety of heterogeneous disease causes and different pathogenesis. These changes lead to increased pulmonary vascular resistance and elevated pulmonary artery pressure, forming a complex clinical and pathophysiological syndrome. Pulmonary hypertension is characterized by pulmonary arteriolar vascular remodeling and pulmonary artery vascular smooth muscle proliferation, which manifests as increased pulmonary circulation pressure and resistance, increased right heart load, right heart failure, and decreased pulmonary blood flow, leading to a series of clinical manifestations; pulmonary hypertension often develops progressively during the course of the disease. In particular, right heart failure caused by increased pulmonary artery vascular tension is a disease that seriously threatens human life and health.

[0003] Pulmonary hypertension mainly affects the pulmonary artery and right heart, manifested by right ventricular hypertrophy and right atrial dilatation. The main trunk of the pulmonary artery is dilated, and the surrounding pulmonary arterioles are sparse. The endothelial cells and smooth muscle cells of the pulmonary arterioles proliferate and hypertrophy, the intima is fibrotic and thickened, the media is thickened, the lumen is narrowed, occluded, twisted and deformed, and plexiform changes occur. The pulmonary venules may also show intimal fibrosis and lumen obstruction. Other manifestations of patients with pulmonary hypertension include hypertrophy of the pulmonary artery adventitia and veins, increased expression of TGF-β, and increased expression of matrix proteins such as elastin, fibronectin, cytochrome C, and mucopolysaccharide.

[0004] Pulmonary hypertension is a treatable disease, but there is no specific cure. Traditional treatments include oxygen inhalation, cardiotonic drugs, diuretics, calcium channel blockers and anticoagulant adjuvant therapy, which mainly relieve symptoms.

[0005] For example, calcium channel blockers, such as nifedipine and diltiazem, can reduce pulmonary vascular resistance and significantly reduce pulmonary artery pressure and resistance at rest and during exercise.

[0006] Endothelin receptor antagonists can dilate pulmonary arteries and improve pulmonary hypertension. Commonly used drugs include: bosentan, ambrisentan, and macitentan.

[0007] Prostacyclin drugs: can dilate blood vessels and reduce pulmonary artery pressure. Long-term use can reverse pulmonary vascular remodeling. Commonly used prostacyclin drugs include epoprostenol, treprostinil injection, beraprost sodium tablets, etc.

[0008] Phosphodiesterase inhibitor-5: can maintain the relaxation state of smooth muscle. Sildenafil, tadalafil, vardenafil and avanafil are representatives of this type of drugs.

[0009] Although these drugs can relieve symptoms to a certain extent, pulmonary arterial hypertension is still an incurable disease with a high mortality rate. The average survival time of patients receiving treatment is only 2.7 years. Currently, there is still a lack of effective cure for pulmonary arterial hypertension. Therefore, it is particularly urgent to find new specific therapeutic drugs. Summary of the invention

[0010] The purpose of the present invention is to provide a pharmaceutical composition for preventing and treating pulmonary hypertension and a preparation method and application thereof.

[0011] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0012] The invention provides a pharmaceutical composition for preventing and treating pulmonary hypertension, comprising the following components: sabutinib, azilsartan, baicalein, sinomenine and danshensu.

[0013] Preferably, the mass ratio of sabutinib, azilsartan, baicalein, sinomenine and danshensu is 65-75:25-35:12-16:20-30:20-30.

[0014] The present invention also provides the use of the pharmaceutical composition in preparing a drug for preventing and / or treating chronic thromboembolic pulmonary hypertension.

[0015] The present invention also provides the use of the pharmaceutical composition in preparing a drug for preventing and / or treating pulmonary hypertension caused by hypoxia.

[0016] The present invention also provides the use of the pharmaceutical composition in preparing a drug for preventing and / or treating pulmonary hypertension caused by lung diseases.

[0017] Preferably, the pulmonary hypertension disease includes chronic obstructive pulmonary disease and interstitial lung disease.

[0018] The present invention also provides a medicine for treating pulmonary hypertension, comprising the medicine composition and auxiliary materials.

[0019] Preferably, the drug for treating pulmonary hypertension is in the form of a solution, a suspension, an emulsion, a granule, a pill or a tablet.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] Among the components added to the composition of the present invention, sabutinib AZD8931 is a reversible, ATP-competitive EGFR inhibitor, which mainly targets the signal transduction of EGFR, ErbB2 and ErbB3. It is a drug that can inhibit the expression of ErbB3 gene, inhibit the expression of ErbB3 gene, significantly inhibit the proliferation of pulmonary artery endothelial cells in patients with pulmonary hypertension, and significantly improve hypoxia-induced PH. ErbB3 inhibitors have been verified to have obvious preventive and therapeutic effects on pulmonary hypertension.

[0022] The UGDH content in the plasma of patients with pulmonary hypertension, as well as in the plasma and lung tissue of rats with pulmonary hypertension, increased significantly, and the content of downstream sugar metabolites D-GlcUA and LMW HA increased. EndoMT index in lung tissue of rats with pulmonary hypertension was upregulated, endothelial cell permeability was increased, and endothelial cell integrity was damaged. If the UGDH gene expression was downregulated, it could significantly improve the EndoMT of pulmonary artery endothelial cells and restore the integrity of endothelial cells; while incubation of pulmonary artery endothelial cells with LMW HA could reverse the effect of UGDH on improving EndoMT, which indicates that UGDH promotes EndoMT of pulmonary artery endothelial cells by regulating the production of LMW HA, destroys the integrity of endothelial cells, participates in pulmonary vascular remodeling, and aggravates the pathological process of pulmonary hypertension. Azilsartan has the effect of inhibiting the expression of UGDH gene-related pathways, and thus plays a corresponding role in pulmonary hypertension and related diseases.

[0023] The baicalein added in the present invention is a natural flavonoid compound, which has anti-inflammatory, anti-proliferative and anti-oxidative effects, and provides endothelial and cardiac protection. Sinomenine has a therapeutic effect on arterial pulmonary hypertension, and can significantly inhibit the increase of pulmonary artery pressure, vascular remodeling and right ventricular hypertrophy. The use of danshensu can significantly reduce the right ventricular pressure and right ventricular hypertrophy index of hypoxic rats, thereby effectively preventing the occurrence of hypoxic pulmonary hypertension in rats.

[0024] The present invention uses the above-mentioned different components in combination and achieves good results in treating pulmonary hypertension. The composition can effectively reduce the pulmonary artery pressure of animal models and can also significantly reduce systemic circulation pressure. Its therapeutic effect is significantly better than that of drugs in the prior art and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0026] Figure 1This is a graph showing the survey results after drug treatment for miniature pigs.

[0027] Figure 2 This is a diagram of the recovery status of the patient in Experimental Example 2. DETAILED DESCRIPTION

[0028] The invention provides a pharmaceutical composition for preventing and treating pulmonary hypertension, comprising the following components: sabutinib, azilsartan, baicalein, sinomenine and danshensu.

[0029] In the present invention, the mass ratio of sabutinib, azilsartan, baicalein, sinomenine and danshensu is 65-75:25-35:12-16:20-30:20-30; preferably 67-73:27-33:13-15:22-28:22-28; further preferably 69-71:29-31:14:24-26:24-26; more preferably 70:30:14:25:25.

[0030] The present invention also provides the use of the pharmaceutical composition in preparing a drug for preventing and / or treating chronic thromboembolic pulmonary hypertension.

[0031] The present invention also provides the use of the pharmaceutical composition in preparing a drug for preventing and / or treating pulmonary hypertension caused by hypoxia.

[0032] The present invention also provides the use of the pharmaceutical composition in preparing a drug for preventing and / or treating pulmonary hypertension caused by lung diseases.

[0033] In the present invention, the pulmonary hypertension diseases include chronic obstructive pulmonary disease and interstitial lung disease.

[0034] The present invention also provides a medicine for treating pulmonary hypertension, comprising the medicine composition and auxiliary materials.

[0035] In the present invention, the dosage form of the drug for treating pulmonary hypertension is a solution, a suspension, an emulsion, a granule, a pill or a tablet.

[0036] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0037] Example 1

[0038] A pharmaceutical composition for preventing and treating pulmonary hypertension comprises the following components: sabutinib, azilsartan, baicalein, sinomenine and danshensu; the mass ratio of sabutinib, azilsartan, baicalein, sinomenine and danshensu is 65:25:12:20:20.

[0039] Example 2

[0040] A pharmaceutical composition for preventing and treating pulmonary hypertension comprises the following components: sabutinib, azilsartan, baicalein, sinomenine and danshensu; the mass ratio of sabutinib, azilsartan, baicalein, sinomenine and danshensu is 75:35:16:30:30.

[0041] Example 3

[0042] A pharmaceutical composition for preventing and treating pulmonary hypertension comprises the following components: sabutinib, azilsartan, baicalein, sinomenine and danshensu; the mass ratio of sabutinib, azilsartan, baicalein, sinomenine and danshensu is 70:30:14:25:25.

[0043] Example 4

[0044] A drug for treating and preventing pulmonary hypertension, comprising the following components in parts by weight:

[0045] 20 parts of the composition obtained in Example 3, 5 parts of sodium carboxymethyl starch, 8 parts of meglumine, 60 parts of lactose, 2 parts of magnesium stearate, 2 parts of 8% hydroxypropyl methylcellulose ethanol aqueous solution by mass concentration, and 4 parts of coating.

[0046] The specific preparation method is as follows:

[0047] (1) The composition obtained in Example 3 and meglumine were mixed uniformly, and the mixture was sieved through a 20-mesh sieve to obtain a mixed material;

[0048] (2) stirring and mixing the mixed material, lactose and 50% of sodium carboxymethyl starch, adding 5-10% of hydroxypropyl methylcellulose ethanol aqueous solution to prepare a soft material, granulating through a 20-mesh sieve, boiling drying, and granulating the dried granules;

[0049] (3) Evenly mix the granules after granulation, the remaining sodium carboxymethyl starch and magnesium stearate, and inspect the semi-finished product;

[0050] (4) Tableting, testing, and coating;

[0051] (5) Finished product inspection and packaging to obtain tablets.

[0052] Control group 1

[0053] A pharmaceutical composition for preventing and treating pulmonary hypertension comprises the following components: baicalein, sinomenine and danshensu; the mass ratio of baicalein, sinomenine and danshensu is 14:25:25.

[0054] Control group 2

[0055] A pharmaceutical composition for preventing and treating pulmonary hypertension comprises the following components: sabutinib, azilsartan and baicalein; the mass ratio of sabutinib, azilsartan and baicalein is 70:30:14.

[0056] Experimental Example 1

[0057] 1. Select 2-2.5 months old, similar weight (5.0-6.0kg), SPF grade miniature pigs for grouping, 6 in each group. That is: blank control group, model group, experimental group, control group 1, control group 2 and prior art group. The feeding conditions are: ambient temperature of 20-22℃; ambient humidity of 50%-55%; light intensity of 25-30lux; it is the normal feeding environment for experimental pigs, without special restrictions.

[0058] Monocrotaline MCT was dissolved with 1mmol / L dilute hydrochloric acid, then adjusted to pH 7.4 with 1mmol / L sodium bicarbonate, and finally diluted with normal saline to a 1% monocrotaline solution. On the first day of the experiment, the model group, the experimental group, the control group 1, the control group 2 and the prior art group were administered subcutaneously via the back of the neck, the miniature pigs were intraperitoneally injected with 60mg / kg of monocrotaline, and the blank control group was injected with an equal amount of normal saline.

[0059] 2. Animal Handling

[0060] After 6 weeks of modeling and feeding, drug administration began. The experimental group (composition obtained by the method of Example 3), control group 1 and control group 2 dissolved the drug and injected it. The dosage was 60 mg / kg body weight for 3 weeks, once a day. The prior art group was captopril, which was administered at 60 mg / kg body weight for 3 weeks, once a day. The blank control group and the model group were injected with the same amount of normal saline.

[0061] Minipigs were anesthetized by intramuscular injection of 6 mg / kg diazepam injection (Tianjin Jinyao Amino Acid Co., Ltd.) + 10 mg / kg sodium pentobarbital solution (Sigma) at the back of the neck. The anesthesia lasted for the entire measurement process (about 1 hour), and the pigs were fasted for 8 hours before anesthesia. The anesthetized minipigs were fixed on the operating table in a supine position, breathing freely, and the chest and limbs were depilated. Echocardiography was used for examination. The specific method is referred to [ZENG GQ, LIU R, LIAO HX, et al. Single intraperitoneal injection of monocrotaline as a novel large animal model of chronic pulmonary hypertension in tibet minipigs [J]. PLoS ONE, 2013, 8 (11): e78965]. Spectral Doppler parameters are as follows. Pulmonary artery systolic pressure (PASP): tricuspid regurgitation pressure gradient plus right atrial pressure (RAP). Pulmonary artery diastolic pressure (PADP): pulmonary valve regurgitation pressure gradient. RAP: Calculate the ratio of tricuspid regurgitation area to right atrial area. When the ratio is <20%, 20% to 50%, and >50%, RAP is estimated to be 5, 10, and 15 mmHg (1 mmHg = 0.133 kPa), respectively. Pulmonary artery mean pressure (PAMP) is calculated as: PAMP = PADP + 1 / 3 (PASP-PADP). Other indicators such as pulmonary valve acceleration time (PAAT), pulmonary valve ejection time (ET), and pulmonary artery pre-ejection period (PEP) are also recorded.

[0062] The method of anesthesia for measuring systemic circulation pressure of miniature pigs was the same as above. After exposing the left internal carotid artery about 20 mm through surgery, a 5F catheter was inserted into the internal carotid artery. The catheter was connected to the calibrated pressure receptor and MedLab to automatically record the systolic, diastolic and mean pressures.

[0063] Table 1 Survey results of miniature pigs after 6 weeks of feeding

[0064]

[0065] It can be seen from the contents recorded in Table 1 that compared with the normal blank control group, after 42 days of administration of monocrotaline, the PASP, PADP, and PAMP indicators of the miniature pigs in the model group, experimental group, control group 1, control group 2, and prior art group were increased, PEP was prolonged, and PAAT and ET were shortened, indicating that each experimental group met the index standard of miniature pig PH and the model was successfully established.

[0066] Table 2 Investigation results after administration to miniature pigs

[0067]

[0068] After 21 days of treatment in each experimental group, pulmonary artery pressure was estimated by echocardiography, and the results are shown in Table 2. Compared with the normal blank control group, the pulmonary artery pressure in the model group was significantly increased, and the pulmonary artery pressure in the treatment group was also increased, but significantly lower than that in the model group. Compared with the prior art group, the therapeutic effect of the experimental group was also better than that of the prior art drugs.

[0069] It can be seen from the data of control group 1 and control group 2 that only by using the complete components of the present invention can the best use effect be achieved. If some of the components are discarded, the use effect of the composition will be significantly affected, especially after sabutinib and azilsartan are discarded, the therapeutic effect of the composition is greatly reduced.

[0070] Experimental Example 2

[0071] The clinical trial statistical results of the present invention are as follows:

[0072] 1. Test subjects: A total of 33 effective cases of pulmonary hypertension were collected, including 13 males and 20 females, with an average age of 31.5 years, an average course of 5.3 years, and a minimum pulmonary artery pressure of 35 mmHg (1 mHg = 0.133 kPa), a maximum of 107 mmHg, and an average of (64.48 plus or minus 14.22) mmHg. Among them, there were 11 cases of idiopathic pulmonary hypertension, 14 cases of chronic thromboembolic pulmonary hypertension, 5 cases of congenital heart disease-related pulmonary hypertension, and 3 cases of connective tissue disease-related pulmonary hypertension.

[0073] Randomly divided into three groups

[0074] 2. Usage and Dosage: Experimental group: take the preparation obtained in Example 4 twice a day, each dose is 50 mg, for two months.

[0075] Prior art group: taking captopril, 12.5 mg per day in the first month, and 50 mg per day in the second month.

[0076] The placebo group took an equal amount of placebo.

[0077] 3. Criteria for determining efficacy

[0078] (1) Cured: The patient's clinical symptoms disappear, including dyspnea, dizziness, chest pain, etc., and the patient's physical condition is restored. All examination indicators are normal.

[0079] (2) Effective: The patient's clinical symptoms were significantly alleviated, and symptoms such as dyspnea, dizziness, and chest pain basically disappeared, and various indicators gradually recovered;

[0080] (3) Ineffective: The patient's clinical symptoms showed no significant or no improvement.

[0081] 4. Treatment results statistics

[0082] Table 3 Treatment status questionnaire

[0083] Group Placebo group Experimental Group Existing Technology Group cure 0 7 6 efficient 0 2 2 invalid 11 2 3

[0084] It can be seen that the composition provided by the present invention has a good therapeutic effect on different types of pulmonary hypertension, and its therapeutic effect is better than that of the drugs in the prior art.

[0085] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A pharmaceutical composition for preventing and treating pulmonary hypertension, characterized in that: The invention comprises the following components: sabutinib, azilsartan, baicalein, sinomenine and danshensu.

2. A pharmaceutical composition for preventing and treating pulmonary hypertension according to claim 1, characterized in that: The mass ratio of sabutinib, azilsartan, baicalein, sinomenine and danshensu is 65-75:25-35:12-16:20-30:20-30.

3. Use of the pharmaceutical composition according to claim 1 or 2 in the preparation of a drug for preventing and / or treating chronic thromboembolic pulmonary hypertension.

4. Use of the pharmaceutical composition according to claim 1 or 2 in the preparation of a drug for preventing and / or treating pulmonary hypertension caused by hypoxia.

5. Use of the pharmaceutical composition according to claim 1 or 2 in the preparation of a drug for preventing and / or treating pulmonary hypertension caused by lung diseases.

6. The use according to claim 5, characterized in that: The pulmonary hypertension diseases include chronic obstructive pulmonary disease and interstitial lung disease.

7. A drug for treating pulmonary hypertension, characterized in that: The invention comprises the pharmaceutical composition according to claim 1 or 2 and auxiliary materials.

8. The drug for treating pulmonary hypertension according to claim 7, characterized in that: The dosage form of the drug for treating pulmonary hypertension is solution, suspension, emulsion, granule, pill or tablet.

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