Pharmaceutical composition for treating cardiovascular diseases and complications thereof, pharmaceutical preparation and preparation method

Abstract

The invention relates to the technical field of pharmaceutical preparations, and discloses a pharmaceutical composition for treating cardiovascular diseases and complications thereof, a pharmaceutical preparation and a preparation method. The pharmaceutical composition provided by the invention contains two active components of lercanidipine hydrochloride and azilsartan, and experimental results show that the pharmaceutical composition has excellent effects on preventing and treating cardiovascular diseases and complications thereof, and can also reduce toxic and side effects of the two components.

Description

Technical Field

[0001] The present application belongs to the technical field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition, a pharmaceutical preparation and a preparation method for treating cardiovascular diseases and their complications. Background Art

[0002] The survey results show that the prevalence of hypertension is generally on the rise. Initial combination therapy for essential hypertension has the advantages of good antihypertensive effect and high safety, and is one of the basic principles of antihypertensive treatment. Single-tablet combination preparations (SPCs) consisting of two or more antihypertensive drugs are easy to use, have high patient compliance, and good medication continuity for the treatment of essential hypertension. The Global Hypertension Practice Guidelines (2023ISH Guidelines) point out that, except for low-risk grade I hypertension and elderly (age > 80 years) or frail patients, other hypertensive patients are recommended to give priority to combination drug treatment.

[0003] The 2023 ISH guidelines state that multiple clinical studies have shown that the blood pressure (BP) goal for most patients with hypertension is <130 / 80 mmHg, and therefore, most patients with hypertension require combination therapy. Although no randomized controlled trials (RCTs) have compared initial combination therapy with monotherapy for major cardiovascular (CV) outcomes, several arguments support the use of a combination of two antihypertensive drugs as initial treatment. First, initial combination therapy is consistently more effective than monotherapy in lowering BP, and even low-dose combination therapy is generally more effective than maximal-dose monotherapy. Furthermore, combination therapy targeting multiple mechanisms reduces the heterogeneity of BP response to initial treatment and provides a steeper dose-response effect than observed with escalating doses of monotherapy. Finally, it is safe and well-tolerated, with no or only a small increase in the risk of hypotensive episodes, even in patients with stage 1 hypertension. Two studies have shown that initial dual-drug combination therapy results in faster BP reduction than monotherapy, and observational evidence suggests that the time to achieve BP control is an important determinant of clinical outcomes, particularly in high-risk patients, where a shorter time to control is associated with a lower risk. Evidence from the more general hypertensive population shows that patients who start dual-drug therapy achieve BP control more frequently after 1 year compared with those who start with monotherapy, possibly because initial combination therapy prevents treatment inertia and is associated with better long-term adherence to and persistence with the prescribed treatment regimen. Studies from large cohorts of patients receiving antihypertensive therapy have also shown that the risk of CV events is lower with initial combination therapy than with a traditional step-wise approach followed by initial monotherapy. In one study, more than 2200 patients who were hospitalized for CV disease during the follow-up period (1 year) could be analyzed, and the switch from initial combination therapy to monotherapy and vice versa was also shown. The results of this within-patient comparison (which excludes the main limitation of observational studies, namely, the comparison to external and potentially different patient groups) showed that the risk of hospitalization was significantly reduced in patients who received combination therapy compared with those who received monotherapy.

[0004] It is recommended to give priority to the use of single-tablet compound form for combined treatment. Currently, compound preparations have a variety of combination methods. Among them, angiotensin-converting enzyme inhibitors (ACEi) / angiotensin receptor blockers (ARB) combined with calcium channel blockers (CCB) have a synergistic antihypertensive effect, which can significantly improve the blood pressure control rate. It is still the optimal combined antihypertensive plan recommended by the 2023 ISH guidelines.

[0005] Currently, single-ingredient preparations of lercanidipine hydrochloride tablets and azilsartan tablets are available on the market, but their combination preparations are not available on the market. Summary of the Invention

[0006] The purpose of this application is to provide a pharmaceutical composition, pharmaceutical preparation and preparation method for treating cardiovascular diseases and their complications.

[0007] In order to achieve the above-mentioned invention objectives, the technical solutions adopted in this application are:

[0008] In a first aspect, the present application provides a pharmaceutical composition for treating cardiovascular diseases and their complications, wherein the pharmaceutical composition comprises, in parts by weight:

[0009] 10-20 parts of lercanidipine hydrochloride and 20-40 parts of azilsartan.

[0010] In a second aspect, the present application provides a pharmaceutical preparation for treating cardiovascular diseases and their complications, wherein the pharmaceutical preparation comprises the above-mentioned pharmaceutical composition.

[0011] In an optional embodiment, the pharmaceutical preparation is a tablet having a single active layer, wherein the single active layer is formed by mixing lercanidipine hydrochloride granules and azilsartan granules and then compressing the mixture.

[0012] In an optional embodiment, the pharmaceutical preparation is a tablet having a double active layer, wherein the double active layer comprises a lercanidipine hydrochloride layer and an azilsartan layer;

[0013] The lercanidipine hydrochloride layer is formed by compressing lercanidipine hydrochloride granules, and the azilsartan layer is formed by compressing azilsartan granules;

[0014] Optionally, the lercanidipine hydrochloride layer and the azilsartan layer are arranged adjacent to each other; or, an isolation layer is provided between the lercanidipine hydrochloride layer and the azilsartan layer.

[0015] In an optional embodiment, the lercanidipine hydrochloride granules comprise lercanidipine hydrochloride and a pharmaceutically acceptable excipient;

[0016] and / or, the azilsartan granules comprise azilsartan and a pharmaceutically acceptable excipient;

[0017] Optionally, the pharmaceutically acceptable excipients include at least one of a filler, microcrystalline cellulose, a disintegrant, a formulation binder, and a lubricant.

[0018] In an optional embodiment, in the lercanidipine hydrochloride granules, the weight of the pharmaceutically acceptable excipient is 4 to 10 parts by weight relative to 1 part by weight of lercanidipine hydrochloride;

[0019] And / or, in the azilsartan granules, the weight of the pharmaceutically acceptable excipient is 2 to 6 parts by weight relative to 1 part by weight of azilsartan.

[0020] In an optional embodiment, in the pharmaceutically acceptable excipients, the weight percentage ratio of the filler, disintegrant, formulation binder and lubricant is (5% to 80%): (1% to 15%): (0.5% to 20%): (0.5% to 10%);

[0021] Optionally, the filler comprises at least one of lactose, lactose monohydrate, corn starch, xylitol and mannitol;

[0022] The disintegrant comprises at least one of cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch;

[0023] The formulation binder includes at least one of polyethylene glycol 6000, mannitol, polyvinyl pyrrolidone and hydroxypropyl cellulose;

[0024] The lubricant includes at least one of colloidal silicon dioxide, hydrated silicon dioxide, magnesium stearate, sodium stearyl fumarate, glyceryl behenate, calcium stearate, stearic acid and talc.

[0025] In a third aspect, the present application provides a method for preparing the aforementioned tablet, comprising the following steps:

[0026] mixing lercanidipine hydrochloride granules with azilsartan granules to obtain a granular mixture;

[0027] Compressing the particle mixture to obtain a first intermediate product;

[0028] The first intermediate product is coated.

[0029] In a fourth aspect, the present application provides a method for preparing the aforementioned tablet, comprising the following steps:

[0030] compressing the lercanidipine hydrochloride granules into a lercanidipine hydrochloride layer;

[0031] Taking the azilsartan granules, and pressing them onto the lercanidipine hydrochloride layer to form an azilsartan layer, to obtain a second intermediate;

[0032] The second intermediate product is coated.

[0033] In a fifth aspect, the present application provides a method for preparing the above-mentioned tablet, comprising the following steps:

[0034] compressing the lercanidipine hydrochloride granules into a lercanidipine hydrochloride layer;

[0035] Taking the isolation layer material, pressing it onto the lercanidipine hydrochloride layer to form an isolation layer;

[0036] taking azilsartan granules and pressing them onto the isolation layer to form an azilsartan layer to obtain a third intermediate;

[0037] The third intermediate product is coated.

[0038] Based on the above technical solution, this application has at least the following beneficial effects:

[0039] (1) The pharmaceutical composition provided in the present application comprises two active ingredients, lercanidipine hydrochloride and azilsartan. Experimental results show that the pharmaceutical composition has excellent effects on the prevention and treatment of cardiovascular diseases and their complications, and can also reduce the toxic side effects of the two ingredients.

[0040] (2) In the composite tablet provided in the present application, lercanidipine hydrochloride and azilsartan exist in an isolated form, which can increase the dissolution rate of the two components while reducing the toxic side effects of the two components. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the following is a brief introduction to the drawings required for use in the specific implementation methods or the description of the prior art. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.

[0042] Figure 1 This is the lercanidipine dissolution curve of the composite tablets obtained in Examples 1-4 of the present application and the commercially available lercanidipine hydrochloride tablets;

[0043] Figure 2 is the azilsartan dissolution curve of the composite tablets obtained in Examples 1-4 of the present application and the commercially available azilsartan tablets;

[0044] Figure 3 This is the lercanidipine dissolution curve of the composite tablets obtained in Examples 5-8 of the present application and the commercially available lercanidipine hydrochloride tablets;

[0045] Figure 4 is the azilsartan dissolution curve of the composite tablets obtained in Examples 5-8 of the present application and the commercially available azilsartan tablets;

[0046] Figure 5 This is the lercanidipine dissolution curve of the composite tablets obtained in Examples 9-12 of the present application and the commercially available lercanidipine hydrochloride tablets;

[0047] Figure 6 is the azilsartan dissolution curve of the composite tablets obtained in Examples 9-12 of the present application and the commercially available azilsartan tablets;

[0048] Figure 7This is the lercanidipine dissolution curve of the composite tablet obtained in the comparative example of the present application and the commercially available lercanidipine hydrochloride tablets;

[0049] Figure 8 This is the azilsartan dissolution curve of the composite tablet obtained in the comparative example of the present application and the commercially available azilsartan tablet. DETAILED DESCRIPTION

[0050] To further illustrate the technical means and results employed by this application to achieve the intended invention objectives, the following describes in detail the specific implementation methods, technical solutions, and features of this application using preferred embodiments. The specific features, structures, or characteristics of the various embodiments described below may be combined in any suitable manner.

[0051] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in this field can be used. If the manufacturer of the reagents or instruments is not specified, they are all commercially available conventional reagents.

[0052] Lercanidipine hydrochloride, chemical name is [3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrobenzene) 2-[(3,3-diphenylpropyl)methylamine]-1,1-dimethylmethyl ester hydrochloride]. The mechanism of action of Lercanidipine hydrochloride is similar to that of similar drugs, which is to reversibly block the Ca2+ of L-type calcium channels in vascular smooth muscle cell membranes. 2+ Lercanidipine promotes inward flow, dilates peripheral blood vessels, and lowers blood pressure. However, it exhibits strong vascular selectivity, a gradual onset of action, a strong antihypertensive effect, a long duration of action, and minimal negative inotropic effects. In vitro studies have shown that lercanidipine has a direct dilating effect on vascular smooth muscle, resulting in a strong antihypertensive effect in vivo, but with minimal effects on heart rate and cardiac output. Due to its large hydrophobic group and strong lipid solubility, lercanidipine is rapidly distributed to tissues and organs after entering the body, tightly binding to vascular smooth muscle cell membranes and releasing slowly. Therefore, although the drug has a short serum elimination half-life, its effects are long-lasting. Lercanidipine hydrochloride is highly safe, has no cardiotonic effect, and does not affect heart rate. It also has excellent anti-atherosclerotic effects, making it particularly suitable for hypertensive patients with atherosclerosis and possessing high clinical application value.

[0053] Azilsartan, chemically known as [2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid], is a novel angiotensin II receptor antagonist (ARB) antihypertensive drug. Currently available on the market are two forms: azilsartan medoxomil and azilsartan, a prodrug of azilsartan. Azilsartan has a high affinity for angiotensin receptor 1 (AT1), 10,000 times greater than its affinity for AT2 receptors, demonstrating significant therapeutic advantages over other ARBs. Studies have shown that azilsartan's peak plasma concentration (cmax) and area under the plasma concentration-time curve (AUC) are dose-dependent. Following oral administration, the time to peak concentration (tmax) ranges from 1.8 to 2.4 hours, and the elimination half-life is approximately 13 hours. Its bioavailability is approximately 60%, and steady-state plasma concentrations are achieved within 5 days after once-daily oral administration. Azilsartan is 99% bound to human plasma proteins (primarily serum albumin), and food does not affect its absorption. Azilsartan is primarily metabolized by CYP2C9 to the inactive major metabolite M-II, and by CYP2B6 and CYP2C8 to the inactive secondary metabolite M-I. Azilsartan has no inhibitory effects on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4, and has no induction effect on CYP3A isoenzymes (in in vitro studies). In addition, azilsartan is an inhibitor of the efflux transporter P-glycoprotein, primarily excreted via feces and kidneys, with a renal excretion rate of 2.3 mL / min. A clinical study examining the effects of gender, age, and race on the pharmacokinetic parameters of azilsartan found that these factors did not affect the pharmacokinetic parameters of azilsartan. Therefore, based on a comprehensive consideration of factors such as the patient's gender, age, liver function, and degree of renal impairment, there is no need to adjust the azilsartan dose. The main adverse reactions to azilsartan include hypotension, dizziness, diarrhea, and hyperkalemia, but these are rare and have a high safety profile.

[0054] Currently, there is no combination preparation of azilsartan and lercanidipine hydrochloride. The combination of the two belongs to the antihypertensive use of angiotensin-converting enzyme inhibitors (ACEi) / angiotensin receptor blockers (ARBs) combined with calcium channel blockers (CCBs). Compared with similar drugs, lercanidipine hydrochloride and azilsartan both have strong selectivity and affinity. In view of this, the present application provides a pharmaceutical composition, pharmaceutical preparation and preparation method for treating cardiovascular diseases and their complications.

[0055] In a first aspect, the present application provides a pharmaceutical composition for treating cardiovascular diseases and their complications, wherein the pharmaceutical composition comprises, in parts by weight, 10 to 20 parts of lercanidipine hydrochloride and 20 to 40 parts of azilsartan.

[0056] Illustratively, the pharmaceutical composition may include a combination of 10 mg of lercanidipine hydrochloride and 20 mg of azilsartan, a combination of 10 mg of lercanidipine hydrochloride and 40 mg of azilsartan, a combination of 20 mg of lercanidipine hydrochloride and 20 mg of azilsartan, or a combination of 20 mg of lercanidipine hydrochloride and 40 mg of azilsartan.

[0057] The cardiovascular disease may be at least one selected from the group consisting of angina pectoris, hypertension, arteriospasm, arrhythmia, cardiac hypertrophy, congestive heart failure, and myocardial infarction.

[0058] In a second aspect, the present application provides a pharmaceutical preparation for treating cardiovascular diseases and their complications, the pharmaceutical preparation comprising the above-mentioned pharmaceutical composition. Exemplarily, the pharmaceutical preparation can be a composite tablet.

[0059] In an optional solution, the composite tablet is a tablet having a single active layer, and the single active layer is formed by mixing lercanidipine hydrochloride granules and azilsartan granules and then compressing them.

[0060] Specifically, lercanidipine hydrochloride granules and azilsartan granules can be prepared separately, mixed, and then the mixture is compressed into tablets to prepare the above-mentioned single-active-layer composite tablet. This composite tablet exhibits improved dissolution of lercanidipine hydrochloride without affecting the dissolution of azilsartan, and has an excellent dissolution effect similar to that of commercially available products.

[0061] Alternatively, the composite tablet comprises a dual active layer comprising a lercanidipine hydrochloride layer and an azilsartan layer. The lercanidipine hydrochloride layer is formed by compressing lercanidipine hydrochloride granules, and the azilsartan layer is formed by compressing azilsartan granules. Exemplarily, the lercanidipine hydrochloride layer and the azilsartan layer are disposed adjacent to each other; alternatively, a barrier layer is provided between the lercanidipine hydrochloride layer and the azilsartan layer.

[0062] Specifically, the dual-active-layer composite tablet can be prepared using a bilayer tablet press by compressing lercanidipine hydrochloride granules into a lercanidipine hydrochloride layer and then compressing azilsartan granules into an azilsartan layer. This composite tablet exhibits excellent dissolution performance similar to that of commercially available products.

[0063] Alternatively, a separator layer can be compressed between the lercanidipine hydrochloride layer and the azilsartan layer to produce a three-layer tablet. The separator layer can be composed, for example, of microcrystalline cellulose. This three-layer tablet also exhibits excellent dissolution performance similar to that of commercially available products.

[0064] The preparation methods of Lercanidipine Hydrochloride Granules and Azilsartan Granules can be selected within a certain range. For example, Lercanidipine Hydrochloride Granules can be obtained by mixing Lercanidipine Hydrochloride with a pharmaceutically acceptable excipient, mixing the mixture for 5 minutes or longer, then wet granulating, and drying the resulting granules. Similarly, Azilsartan Granules can be obtained by mixing Azilsartan with a pharmaceutically acceptable excipient, mixing the mixture for 5 minutes or longer, then wet granulating, and drying the resulting granules.

[0065] The present application is further described in detail below with reference to specific embodiments. These embodiments should not be construed as limiting the scope of protection claimed in this application.

[0066] Examples 1 to 4

[0067] A single-layer composite tablet with a single active layer was prepared. The raw materials and amounts used to prepare lercanidipine hydrochloride granules and azilsartan granules are recorded in Table 1. According to the records in Table 1, purified water was used as a solvent, and lercanidipine hydrochloride granules and azilsartan granules were prepared by wet granulation and dried. The two granules were mixed and pressed into composite tablets, which were then film-coated. Due to the instability of azilsartan, hydroxypropyl cellulose or other common adhesives can be used in the preparation of azilsartan granules. The solution is dissolved in water with polyethylene glycol 6000 or mannitol to form a solution, which is then added by atomization. Azilsartan is subjected to airflow pulverization using an inert gas as a gas source, which can reduce the risk of a sharp increase in degradation impurities after azilsartan is pulverized.

[0068] Table 1 Raw materials and amounts involved in Examples 1-4

[0069]

[0070] The composite tablets obtained in Examples 1-4 were compared with commercially available lercanidipine hydrochloride tablets 10 mg (Zaininping) and azilsartan tablets 20 mg (Takeda) for dissolution curve testing.

[0071] The dissolution profile of lercanidipine hydrochloride was determined according to the dissolution and release assay method (General Method 0931, Method 2), using 900 ml of 0.1 mol / L hydrochloric acid solution as the dissolution medium at a rotation speed of 50 rpm. The dissolution results were analyzed by high-performance liquid chromatography (HPLC) using octadecylsilane-bonded silica gel as the packing (Waters Nova-Pak, 300 × 3.9 mm, 4 μm or equivalent columns), acetonitrile / sodium perchlorate buffer (pH 3.0) (60 / 40) as the mobile phase, and detection at a wavelength of 240 nm.

[0072] Test results such as Figure 1As shown in the results, after isolation granulation, the in vitro dissolution of lercanidipine hydrochloride in the prepared lercanidipine hydrochloride and azilsartan composite tablets had no significant difference from that of the commercially available lercanidipine hydrochloride tablets (Zaininping), and the similarity was greater than 50.

[0073] The dissolution curve test of azilsartan was carried out according to the dissolution test method (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0931 Second Method), using 900 ml of 0.5% sodium lauryl sulfate as the dissolution medium, a rotation speed of 50 revolutions per minute, and UV-visible spectrophotometry (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0401) at a wavelength of 245 nm.

[0074] Test results such as Figure 2 As shown in the results, after isolation granulation, the in vitro dissolution of azilsartan in the prepared lercanidipine hydrochloride and azilsartan composite tablets had no significant difference from that of the commercially available azilsartan tablets, and the similarities were both greater than 50.

[0075] Examples 5 to 8

[0076] A bilayer composite tablet with two active layers was prepared. The raw materials and amounts used to prepare lercanidipine hydrochloride granules and azilsartan granules are listed in Table 2. According to the information in Table 2, lercanidipine hydrochloride granules and azilsartan granules were prepared by wet granulation using purified water as the solvent and then dried. The two granules were mixed and compressed into a bilayer solid form, which was then film-coated.

[0077] Table 2 Raw materials and amounts involved in Examples 5-8

[0078]

[0079] The composite tablets obtained in Examples 5-8 were compared with commercially available lercanidipine hydrochloride tablets 10 mg (Zaininping) and azilsartan tablets 20 mg (Takeda) for dissolution curve testing. The testing method was the same as that described in Examples 1-4.

[0080] Dissolution curve test of lercanidipine hydrochloride Figure 3 As shown, the in vitro dissolution of lercanidipine hydrochloride in the lercanidipine hydrochloride and azilsartan composite tablets prepared in Examples 5-8 had no significant difference from that of the commercially available lercanidipine hydrochloride tablets (Zaininping), and the similarities were greater than 50.

[0081] Azilsartan dissolution curve test Figure 4 As shown, the in vitro dissolution of azilsartan in the lercanidipine hydrochloride and azilsartan composite tablets prepared in Examples 5-8 had no significant difference from that of the commercially available azilsartan tablets, and the similarities were greater than 50.

[0082] Examples 9 to 12

[0083] A three-layer composite tablet with two active layers was prepared. The raw materials and amounts used to prepare lercanidipine hydrochloride granules and azilsartan granules are listed in Table 3. According to the information in Table 3, lercanidipine hydrochloride granules and azilsartan granules were prepared by wet granulation using purified water as the solvent and then dried. Azilsartan granules were prepared to form the first tablet layer, a separator was added to form the second tablet layer, and lercanidipine hydrochloride granules were added to form the third tablet layer. Finally, the three-layer composite tablet was obtained and film-coated.

[0084] Table 3 Raw materials and amounts involved in Examples 9-12

[0085]

[0086] The tablets obtained in Examples 9-12 were compared with commercially available lercanidipine hydrochloride tablets 10 mg (Zanipian) and azilsartan tablets 20 mg (Takeda) for dissolution curve testing. The testing method was the same as that described in Examples 1-4.

[0087] Dissolution curve test of lercanidipine hydrochloride Figure 5 As shown, the in vitro dissolution of lercanidipine hydrochloride in the lercanidipine hydrochloride and azilsartan composite tablets prepared in Examples 5-8 had no significant difference from that of the commercially available lercanidipine hydrochloride tablets (Zaininping), and the similarities were greater than 50.

[0088] Azilsartan dissolution curve test Figure 6 As shown, the in vitro dissolution of azilsartan in the lercanidipine hydrochloride and azilsartan composite tablets prepared in Examples 5-8 had no significant difference from that of the commercially available azilsartan tablets, and the similarities were greater than 50.

[0089] Comparative Example

[0090] Composite tablets with a single active layer were prepared. The raw materials and amounts involved are listed in Table 4. Granules containing both lercanidipine hydrochloride and azilsartan were prepared by wet granulation using purified water as the solvent according to Table 4 and then dried. The resulting granules were then compressed into composite tablets and film-coated.

[0091] Table 4 Raw materials and dosage involved in comparative examples

[0092]

[0093] The tablets obtained in the comparative example were compared with commercially available lercanidipine hydrochloride tablets 10 mg (Zaininping) and azilsartan tablets 20 mg (Takeda) for dissolution curve testing. The testing method was the same as described in Examples 1-4.

[0094] Dissolution curve test of lercanidipine hydrochloride Figure 7As shown, the in vitro dissolution of lercanidipine hydrochloride in the lercanidipine hydrochloride and azilsartan composite tablets prepared in the comparative example was significantly different from that of the commercially available lercanidipine hydrochloride tablets (Zaininping).

[0095] Azilsartan dissolution curve test Figure 8 As shown, the in vitro dissolution of azilsartan in the lercanidipine hydrochloride and azilsartan composite tablets prepared in the comparative example was significantly different from that of the commercially available azilsartan tablets.

[0096] Test Case

[0097] To test the therapeutic effect of the combination therapy of lercanidipine hydrochloride and azilsartan in rats.

[0098] 13-week-old male SHR rats (spontaneously hypertensive rats, Orient) were acclimated and domesticated for one week, while maintaining a temperature range of 22-24°C and a humidity range of 50-70%, with a light-dark cycle of 12 hours. One day before administration, the blood pressure and heart rate of the test animals were measured using a BP-2000 blood pressure analysis system (Visitech). After measurement, the animals were fasted for approximately 12 hours, during which time drinking water was provided ad libitum. Various test drugs were then orally administered to the fasted test animals at a volume of 5 ml / kg. The test drugs, lercanidipine hydrochloride and azilsartan, were dissolved in 20% 2-hydroxypropyl B-cyclodextrin (HPCD).

[0099] The combination therapy group (N=10) was administered with 2 mg / kg of lercanidipine hydrochloride and 4 mg / kg of azilsartan. Monotherapy group A (N=10) was administered with 8 mg / kg of azilsartan. Monotherapy group B was administered with 4 mg / kg of lercanidipine hydrochloride. The negative control group received the same volume of vehicle orally.

[0100] One hour after administration, the blood pressure and heart rate of the rats in each group were measured and then statistically calculated. Statistical calculations were performed using one-way ANOVA to analyze the significant differences between the test group and the control group, and between the combination therapy group and the monotherapy group. The results are shown in Table 5.

[0101] Table 5 The therapeutic effects of each test group on rats

[0102]

[0103] The above description is merely a preferred embodiment of the present application; however, the scope of protection of the present application is not limited thereto. Any person skilled in the art who, within the technical scope disclosed in the present application, makes equivalent substitutions or modifications based on the technical solutions and improved concepts of the present application shall be covered by the scope of protection of the present application.

Claims

1. A pharmaceutical composition for treating cardiovascular diseases and their complications, characterized in that: In parts by weight, the pharmaceutical composition comprises: 10-20 parts of lercanidipine hydrochloride and 20-40 parts of azilsartan.

2. A pharmaceutical preparation for treating cardiovascular diseases and their complications, characterized in that: The pharmaceutical preparation comprises the pharmaceutical composition according to claim 1.

3. The pharmaceutical preparation according to claim 2, characterized in that The pharmaceutical preparation is a tablet having a single active layer, wherein the single active layer is formed by mixing lercanidipine hydrochloride granules and azilsartan granules and then compressing the mixture.

4. The pharmaceutical preparation according to claim 2, characterized in that The pharmaceutical preparation is a tablet having a double active layer, wherein the double active layer comprises a lercanidipine hydrochloride layer and an azilsartan layer; The lercanidipine hydrochloride layer is formed by compressing lercanidipine hydrochloride granules, and the azilsartan layer is formed by compressing azilsartan granules; Optionally, the lercanidipine hydrochloride layer and the azilsartan layer are arranged adjacent to each other; or, an isolation layer is provided between the lercanidipine hydrochloride layer and the azilsartan layer.

5. The pharmaceutical preparation according to claim 3 or 4, characterized in that The lercanidipine hydrochloride granules comprise lercanidipine hydrochloride and a pharmaceutically acceptable excipient; and / or, the azilsartan granules comprise azilsartan and a pharmaceutically acceptable excipient; Optionally, the pharmaceutically acceptable excipients include at least one of a filler, microcrystalline cellulose, a disintegrant, a formulation binder, and a lubricant.

6. The pharmaceutical preparation according to claim 5, characterized in that In the lercanidipine hydrochloride granules, the weight of the pharmaceutically acceptable excipient is 4 to 10 parts by weight relative to 1 part by weight of lercanidipine hydrochloride; And / or, in the azilsartan granules, the weight of the pharmaceutically acceptable excipient is 2 to 6 parts by weight relative to 1 part by weight of azilsartan.

7. The pharmaceutical preparation according to claim 5 or 6, characterized in that In the pharmaceutically acceptable excipients, the weight percentage ratio of the filler, disintegrant, formulation binder and lubricant is (5% to 80%): (1% to 15%): (0.5% to 20%): (0.5% to 10%); Optionally, the filler comprises at least one of lactose, lactose monohydrate, corn starch, xylitol and mannitol; The disintegrant comprises at least one of cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch; The formulation binder includes at least one of polyethylene glycol 6000, mannitol, polyvinyl pyrrolidone and hydroxypropyl cellulose; The lubricant includes at least one of colloidal silicon dioxide, hydrated silicon dioxide, magnesium stearate, sodium stearyl fumarate, glyceryl behenate, calcium stearate, stearic acid and talc.

8. The method for preparing the tablet according to claim 3, wherein: The steps include: mixing lercanidipine hydrochloride granules with azilsartan granules to obtain a granular mixture; pressing the particle mixture to obtain a first intermediate product; The first intermediate product is coated.

9. The method for preparing the tablet according to claim 4, characterized in that: The steps include: compressing the lercanidipine hydrochloride granules into a lercanidipine hydrochloride layer; Taking the azilsartan granules, and pressing them onto the lercanidipine hydrochloride layer to form an azilsartan layer, to obtain a second intermediate; The second intermediate product is coated.

10. The method for preparing the tablet according to claim 4, characterized in that: The steps include: compressing the lercanidipine hydrochloride granules into a lercanidipine hydrochloride layer; Taking the isolation layer material, pressing it onto the lercanidipine hydrochloride layer to form an isolation layer; taking azilsartan granules and pressing them onto the isolation layer to form an azilsartan layer to obtain a third intermediate; The third intermediate product is coated.

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