Gastric retention double-layer sustained release tablet as well as preparation method and application thereof

Abstract

The invention discloses a gastric retention double-layer sustained-release tablet and a preparation method and application thereof, and belongs to the field of pharmaceutical preparations, the active ingredient of the gastric retention double-layer sustained-release tablet is 3-[4-[4-(lH-benzotriazole-1-yl) butyl] piperazine-1-yl] benzisothiazole hydrochloride, and the gastric retention double-layer sustained-release tablet is composed of a quick-release drug release layer and a sustained-release drug release layer, the quick release layer contains an active component, a filler I and a disintegrating agent; and the sustained-release layer contains an active component, a filler II, an expansion material, a release retardant, an expansion accelerator and a stabilizer. According to the gastro-retention double-layer sustained-release tablet, the quick-release layer can quickly release the medicine to reach the effective blood concentration, and the retention time of the tablet in the stomach is prolonged after the sustained-release layer expands, so that the in-vivo absorption window of the medicine is prolonged, the maintenance of the blood concentration is realized, the in-vivo half-life period of active ingredients is remarkably prolonged, the administration frequency can be reduced, and the compliance of a patient is improved. The product is simple in preparation process, suitable for industrial production and wide in development prospect.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations and relates to a gastric retention double-layer sustained-release tablet and a preparation method and application thereof. Background Art

[0002] 3-[4-[4-(1H-benzotriazole-1-yl)butyl]piperazine-1-yl]benzisothiazole hydrochloride can antagonize 5-HT 2A receptors, while blocking α 1A Receptor, also has calcium channel blocking effect. Pharmacological efficacy tests show that it has good therapeutic effects on diseases such as hypertension, pulmonary hypertension, benign prostatic hyperplasia, etc. (CN103833658A, application number 202411785128.3). However, pharmacokinetic studies have shown that the half-life of this compound in animals and humans is short, and the drug concentration in plasma decreases significantly after 12 hours. The blood drug concentration can only be maintained by multiple daily administrations, which will bring great inconvenience to patients.

[0003] According to experimental studies, the absorption of the compound in the gastrointestinal tract is uneven, and the absorption in the intestine is weak, resulting in a short absorption window in the body. Conventional double-layer sustained-release tablets and multi-unit granules cannot maintain long-term continuous absorption after slow release in the body, making it difficult to achieve once-a-day dosing (QD). This makes the development of sustained-release tablets that can be administered QD a technical difficulty. Summary of the invention

[0004] The technical problem to be solved by the present invention is to design, study and provide a gastric retentive double-layer sustained-release tablet containing 3-[4-[4-(lH-benzotriazole-1-yl)butyl]piperazine-1-yl]benzisothiazole hydrochloride (codenamed MT-1207) and its preparation method and application in view of the above-mentioned deficiencies. The gastric retentive double-layer sustained-release tablet can fully absorb gastric juice after oral administration and swell to form a hydrogel, which not only controls the drug release rate, but also the hydrogel preparation that absorbs water and swells can produce a gastric retention effect through the comprehensive effects of floating, mucosal adhesion and swelling volume, etc., and exhibits a sustained release effect of more than 16 hours both in vivo and in vitro and good absorption in Beagle dogs, achieving once-a-day dosing and increasing patients' compliance with medication. At the same time, the gastric retentive sustained-release tablet is prepared by a dry granulation process, which is simple in process and conducive to industrial production.

[0005] The gastric retention double-layer sustained-release tablet of the present invention comprises two drug release layers, namely, an immediate-release layer and a sustained-release layer. The immediate-release layer comprises an active ingredient, 3-[4-[4-(1H-benzotriazole-1-yl)butyl]piperazine-1-yl]benzisothiazole hydrochloride (codenamed MT-1207), a filler I, and a disintegrant; the sustained-release layer comprises an active ingredient, 3-[4-[4-(1H-benzotriazole-1-yl)butyl]piperazine-1-yl]benzisothiazole hydrochloride (codenamed MT-1207), a filler II, an expansion material, a release retardant, an expansion promoter, and a stabilizer.

[0006] In the gastric retentive double-layer sustained-release tablet of the present invention, the quick-release layer filler I is one or more of microcrystalline cellulose, lactose and starch, and its content is 8%-35% of the total weight of the gastric retentive double-layer sustained-release tablet.

[0007] The gastric retentive double-layer sustained-release tablet of the present invention, wherein the quick-release layer disintegrant is one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch, and the content thereof is 0.3%-3% of the total weight of the gastric retentive double-layer sustained-release tablet.

[0008] The gastric retentive double-layer sustained-release tablet of the present invention, wherein the sustained-release layer filler II is one or more of microcrystalline cellulose, lactose, starch, and pregelatinized starch, and its content is 5%-35% of the total weight of the gastric retentive double-layer sustained-release tablet.

[0009] The gastric retentive double-layer sustained-release tablet of the present invention comprises a sustained-release layer expansion material of polyethylene oxide, the content of which is 8%-50% of the total weight of the gastric retentive double-layer sustained-release tablet.

[0010] The molecular weight of the polyoxyethylene described in the present invention is 1×10 6 Up to 7×10 6 .

[0011] The gastric retentive double-layer sustained-release tablet of the present invention, wherein the release retardant of the sustained-release layer is one or more of hypromellose K4M, hypromellose K15M, hypromellose K100M, hypromellose K100LV, ethyl cellulose, carbomer, methacrylic acid-methyl methacrylate copolymer, and the content thereof is 0%-30% of the total weight of the gastric retentive double-layer sustained-release tablet.

[0012] The gastric retentive double-layer sustained-release tablet of the present invention, wherein the sustained-release layer swelling promoter is one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch, and the content thereof is 13%-35% of the total weight of the gastric retentive double-layer sustained-release tablet.

[0013] The gastric retentive double-layer sustained-release tablet of the present invention, wherein the sustained-release layer stabilizer is one or more of butylated hydroxytoluene, propyl gallate, ascorbic acid, anhydrous citric acid, tartaric acid, sodium pyrosulfite, and disodium edetate, and the content thereof is 0%-5% of the total weight of the gastric retentive double-layer sustained-release tablet.

[0014] The gastric retentive double-layer sustained-release tablet of the present invention further comprises a lubricant, which is one or more of talc, stearic acid, magnesium stearate and colloidal silicon dioxide, and its content is 0.01%-2% of the total weight of the gastric retentive double-layer sustained-release tablet.

[0015] The gastric retentive double-layer sustained-release tablet of the present invention may further comprise coating ingredients, such as polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, and acrylic resin.

[0016] The method for preparing the gastric retentive double-layer sustained-release tablet of the present invention comprises the following steps:

[0017] Preparation of immediate-release granules: Mix the immediate-release layer raw materials and auxiliary materials except the lubricant evenly, use a dry granulator to perform dry granulation, add the lubricant and mix evenly to obtain the immediate-release layer mixed powder.

[0018] Preparation of sustained-release granules: Mix the raw and auxiliary materials of the sustained-release layer except the lubricant evenly, use a dry granulator to perform dry granulation, add the lubricant and mix evenly to obtain a sustained-release layer mixed powder.

[0019] Tablet compression: First, lightly compress the sustained-release layer granules into loose tablets, then add the immediate-release layer granules and press into shape to obtain gastric retentive double-layer sustained-release tablets.

[0020] The invention discloses an application of the gastric retention double-layer sustained-release tablet in preparing drugs for treating diseases such as hypertension, pulmonary hypertension, and benign prostatic hyperplasia.

[0021] Beneficial effects of the present invention:

[0022] The gastric retention double-layer sustained-release tablet of the present invention has a quick-release layer that can quickly release the drug to achieve an effective blood drug concentration, and the sustained-release layer expands to prolong the retention time of the tablet in the stomach, thereby prolonging the drug absorption window in the body to achieve the maintenance of blood drug concentration, significantly prolonging the half-life of MT-1207 in the body, reducing the number of drug administrations and increasing patient compliance. The preparation process of this product is simple, suitable for industrial production, and has broad development prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 Dissolution curves of the products of Examples 1-4.

[0024] Figure 2 Dissolution curves of the products of Examples 5-8.

[0025] Figure 3Product dissolution curves of Examples 9-10, 12 and Comparative Examples 1-3.

[0026] Figure 4 Drug concentration curves in plasma of Examples 9-10 and Comparative Examples 1-3.

[0027] Figure 5 Blood concentration curve of oral MT-1207 API in dogs.

[0028] Figure 6 Comparative Example 4 shows the blood drug concentration curve of a single-dose test in healthy subjects. DETAILED DESCRIPTION

[0029] Several embodiments are listed below to illustrate the technical solutions of the present invention. The following embodiments are preferred implementations of the present invention, but the implementations of the present invention are not limited to the following embodiments.

[0030] Example 1-4: Preparation of MT-1207 Immediate Release Layer Tablet

[0031] According to the ingredients and the contents of each ingredient listed in Table 1 below, MT-1207 immediate-release layer tablets were prepared. The preparation process is as follows:

[0032] The raw materials and auxiliary materials except the lubricant are mixed for 15 minutes, and dry granulation is performed using a dry granulator. The lubricant is added and mixed for 5 minutes to obtain a mixed powder for the immediate release layer, and tablets are obtained.

[0033] Table 1 Prescription composition of Examples 1-4

[0034]

[0035] Powder fluidity test method: Use a measuring cylinder and a tap density tester to test the bulk density and tap density of the particles respectively, and calculate the Carr index.

[0036] The particle size distribution of the particles was tested by dry method using a laser particle size distribution analyzer with a dispersion pressure of 1.5 bar.

[0037] Take this product, according to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Second Method), use pH 1.0 hydrochloric acid as the medium, the speed is 75 revolutions per minute, operate according to the law, take samples at 5, 10, 15, 30, 45, 60 minutes and calculate the cumulative dissolution. The results are shown in Table 2, and the dissolution curve is shown in Figure 1 .

[0038] Table 2 Cumulative dissolution and particle characterization results of Examples 1-4

[0039]

[0040] As shown in Table 2, the rapid-release granules prepared in Examples 1-4 have good fluidity, and the tablets can be rapidly dissolved in an acidic medium, providing a guarantee for the rapid early release of the MT-1207 gastric retentive double-layer sustained-release tablets.

[0041] Example 5-8: Preparation of MT-1207 sustained-release layer tablets

[0042] According to the ingredients and the contents of each ingredient listed in Table 3 below, MT-1207 sustained-release layer tablets were prepared. The preparation process is as follows:

[0043] The raw materials and auxiliary materials except the lubricant are mixed for 15 minutes, and dry granulated by a dry granulator. The lubricant is added and mixed for 5 minutes to obtain a mixed powder for a sustained-release layer, and tablets are obtained.

[0044] Table 3 Prescription composition of Examples 5-8

[0045]

[0046] Powder fluidity test method: Use a measuring cylinder and a tap density tester to test the bulk density and tap density of the particles respectively, and calculate the Carr index.

[0047] Take this product, according to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part Four General Rules 0931 Second Method), the instrument device uses a homemade sinker, pH 4.0 ABS solution as the medium, the speed is 75 revolutions per minute, operate according to the law, take samples at 1, 2, 4, 6, 8, 12, 16, 24 hours and calculate the cumulative dissolution. Use a dissolution instrument, with 900mL of 37°C pH4.0 ABS solution as the medium, test the expansion size at different time points and calculate the expansion rate. The results are shown in Table 4, and the dissolution curve is shown in Figure 2 .

[0048] Expansion rate = expanded volume / initial volume*100%;

[0049] Volume = major diameter * minor diameter * thickness (volume is only a rough calculation).

[0050] Table 4 Cumulative dissolution and swelling rate data of Examples 5-8

[0051]

[0052] As shown in Table 4, Examples 5-8 can all achieve slow and sustained release within 24 hours, and all have good swelling performance, and can maintain a swelling rate of more than 160% within 6 hours.

[0053] Stabilizer inspection test:

[0054] The sustained-release layer mixed powder prepared in Example 8 was mixed with different stabilizers in a certain proportion and placed in an open container or in a bottle at 40°C and 75% RH to examine the changes in the content and related substances. The results showed that each stabilizer had a stabilizing effect on the sustained-release layer mixed powder to varying degrees.

[0055] Table 5 Stabilizer investigation results

[0056]

[0057] Example 9-12: Preparation of MT-1207 gastric retentive double-layer sustained-release tablets

[0058] According to the ingredients and the content of each ingredient listed in Table 6 below, MT-1207 gastric retention double-layer sustained-release tablets were prepared, and the preparation process was as follows:

[0059] The raw materials and auxiliary materials except the lubricant are mixed for 15 minutes, dry granulated by a dry granulator, and the lubricant is added and mixed for 5 minutes to obtain mixed powders of the immediate-release layer and the sustained-release layer respectively, and tablets are obtained by using a double-layer tablet press.

[0060] Comparative Example 1: Preparation of conventional MT-1207 double-layer sustained-release tablets

[0061] According to the ingredients and the contents of each ingredient listed in Table 6 below, MT-1207 conventional double-layer sustained-release tablets were prepared. The preparation process is as follows:

[0062] The raw materials and auxiliary materials except the lubricant are mixed for 15 minutes, dry granulated by a dry granulator, and the lubricant is added and mixed for 5 minutes to obtain mixed powders of the immediate-release layer and the sustained-release layer respectively, and tablets are obtained by using a double-layer tablet press.

[0063] Table 6 Prescription composition of Examples 9-12 and Comparative Example 1

[0064]

[0065] Comparative Example 2-3: Preparation of enteric-coated MT-1207 granules

[0066] According to the ingredients and the contents of each ingredient listed in Table 7 below, the micro-pellets were drug-coated and coated using a fluidized bed. The tartaric acid pellet cores were drug-coated and coated with an isolation layer to obtain immediate-release pellet cores; the immediate-release pellet cores were used to prepare MT-1207 sustained-release pellet cores with different sustained-release coating weights, and the immediate-release pellet cores and the sustained-release pellet cores with different coating weights were canned in enteric-coated gelatin capsules as shown in the table, and each capsule contained 60 mg MT-1207.

[0067] Table 7 Prescription composition of Comparative Example 2-3

[0068]

[0069] *Film coating premix (gastric soluble): purchased from Shanghai Colorcon Coating Technology Co., Ltd., model number is Opadry 03K19229-CN transparent.

[0070] Take this product, and according to the dissolution and release determination method (Method 2 of Part IV of the Chinese Pharmacopoeia 2020 Edition, General Rules 0931, Part IV), the MT-1207 enteric-coated granules were subjected to a two-stage medium release test in pH 1.0 hydrochloric acid solution and artificial simulated fasting intestinal fluid (FaSSIF); MT-1207 conventional double-layer sustained-release tablets and MT-1207 gastric retentive double-layer sustained-release tablets were tested for release using pH 4.0 ABS solution as the medium. The rotation speed is 75 revolutions per minute, and the cumulative dissolution is calculated. Using a dissolution instrument, using 900 mL of 37°C pH 4.0 ABS solution as the medium, the expansion size of the gastric retentive double-layer sustained-release tablets was tested at different time points, and the expansion rate was calculated. The results are shown in Tables 8 and 9, and the dissolution curves are shown in Tables 8 and 9. Figure 3 .

[0071] Table 8 Expansion rate data of Examples 9-12

[0072]

[0073] Table 9 Cumulative dissolution data of Examples 9, 10, 12 and Comparative Examples 1-3

[0074]

[0075]

[0076] As shown in Table 8 and Table 9, the gastric retentive double-layer sustained-release tablets prepared in Examples 9-12 can achieve slow and sustained release within 24 hours, and the swelling performance is good.

[0077] Beagel dog pk test:

[0078] Examples 9-10 are gastric retentive double-layer sustained-release tablets, and Comparative Example 1 is a conventional double-layer sustained-release tablet. A postprandial test was used. The drug was administered half an hour after an equal amount of food was given, and blood was collected at 0.25, 0.5, 1, 2, 4, 8, 10, 12, 16, 20, and 24 hours to detect plasma drug concentrations. Comparative Examples 2-3 are enteric-coated granules. A fasting test was used. Pentagastrin was administered before administration, and food was given 4 hours after administration. Blood was collected at 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours to detect plasma drug concentrations. Half of the males and half of the females were males. Pharmacokinetic parameters are shown in Table 10, and drug concentrations in plasma are shown in Table 10. Figure 4 .

[0079] The results showed that the blood concentration of conventional double-layer sustained-release tablets and enteric-coated granules dropped rapidly after reaching the peak in about 1 to 3 hours, and no obvious absorption was observed after 8 hours. The blood concentration of gastric retentive double-layer sustained-release tablets could be maintained for 12 to 16 hours, and could still reach nearly 30 ng / mL after 12 hours, with significantly better effects and more stable blood concentrations.

[0080] Table 10 Canine pk test results of Examples 9-10 and Comparative Examples 1-3

[0081]

[0082] The MT-1207 API was used to conduct a dog PK test. The subjects were fasted for 12 hours before the experiment. Blood was collected at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, and 24 hours after oral administration to detect the plasma drug concentration. Half of the subjects were male and half were female (a total of 8). The results showed that the drug concentration in plasma decreased significantly after 12 hours. For details, see Figure 5 .

[0083] Comparative Example 4: Preparation of MT-1207 Immediate Release Tablets

[0084] According to the ingredients and the content of each ingredient listed in Table 11 below, MT-1207 immediate-release tablets were prepared using wet granulation and tableting technology.

[0085] Healthy volunteers were selected and took a single oral dose of 5mg, 10mg, 20mg, and 40mg immediate-release tablets after fasting overnight. Blood was collected at 5min, 10min, 15min, 30min, 1, 1.5, 2, 4, 6, 8, 12, 24, 24, and 48h to detect plasma drug concentration. The results showed that the drug concentration in plasma decreased significantly after 12h. Pharmacokinetics are shown in Table 12, and the drug concentration in plasma is shown in Figure 6 .

[0086] 1) Research subjects

[0087] Inclusion criteria: (1) male and female subjects aged 18 to 55 years (inclusive); (2) male subjects weighing no less than 50 kg and female subjects weighing no less than 45 kg. Body mass index (BMI) = weight (kg) / height squared (m

[0088] 2 ), body mass index between 18 and 28 kg / m 2 range (including critical values); (3) the subjects (including their partners) are willing to voluntarily take effective contraceptive measures from screening to 6 months after the last administration of study drugs; (4) physical examination and vital signs are normal or abnormal with no clinical significance.

[0089] Exclusion criteria: (1) Smokers who smoked more than 5 cigarettes a day in the three months before the trial; (2) Allergic constitution (multiple drug and food allergies); (3) History of drug abuse and / or alcoholism (drinking 14 units of alcohol per week: 1 unit = 285 mL of beer, or 25 mL of spirits, or 100 mL of wine); (4) Blood donation or massive blood loss (>450 mL) within three months before screening; (5) Taking any medication that alters liver enzyme activity within 28 days before screening; (6) Taking any prescription drugs, over-the-counter drugs, any vitamin products or herbal medicines within 14 days before screening; (7) Taking special diets (including (8) Those who have consumed the following CYP3A4, P-gp or Bcrp inhibitors or inducers, such as itraconazole, ketoconazole or dronedarone; (9) Those who have recently had major changes in their diet or exercise habits; (10) Those who have taken study drugs or participated in drug clinical trials within three months before taking study drugs; (11) Those who have a history of dysphagia or any gastrointestinal disease that affects drug absorption; (12) Those who suffer from any disease that increases the risk of bleeding, such as hemorrhoids, acute gastritis or gastric and duodenal ulcers. ulcer, etc.; (13) ECG abnormalities are clinically significant, QTC>450ms; (14) Sitting systolic blood pressure is less than 100mmHg, and / or sitting diastolic blood pressure is less than 60mmHg; (15) Postural hypotension occurs during screening; (16) There is a history of postural hypotension or syncope; (17) Female subjects are in the lactation period or serum pregnancy test is positive during the screening period or the trial; (18) Clinical laboratory tests have clinically significant abnormalities, or other clinical findings within 12 months before screening show clinically significant diseases (including but not limited to gastrointestinal, kidney, liver, nerve, blood, endocrine, tumor, (1) Positive screening results for viral hepatitis (including hepatitis B and C), HIV antibody, or Treponema pallidum antibody; (20) Acute illness or concomitant medication from the screening stage to the study medication; (21) Consumption of chocolate, any caffeinated or xanthine-rich food or beverage within 48 hours before taking the study medication; (22) Consumption of any alcoholic product within 48 hours before taking the study medication; (23) Positive urine drug screen or history of drug abuse or use of drugs in the past five years; (24) Subjects who are considered by the investigator to have other factors that are not suitable for participation in this trial.

[0090] 2) Statistical processing

[0091] Phoenix WinNonlin (version 7.0 and above) software was used to calculate AUC using the non-compartmental model method. 0-t , AUC 0-∞ , C max And other main pharmacokinetic parameters.

[0092] 3) Safety evaluation

[0093] During the trial, the subjects underwent the following safety checks: vital signs (respiration and body temperature, systolic and diastolic blood pressure), 12-lead electrocardiogram, orthostatic hypotension, ECG monitoring, laboratory tests (blood biochemistry, routine blood and urine tests), symptoms and physical examination, and the entire medication process was evaluated and adverse drug events were followed up.

[0094] Table 11 Comparative Example 4 Immediate Release Tablets Prescription Composition

[0095] Element Comparative Example 4 (mg / tablet) MT-1207 10 lactose 90 Microcrystalline Cellulose 90 Povidone K30 14 Crospovidone 6 Silicon dioxide 2 Magnesium Stearate 0.6

[0096] Table 12 Summary of pharmacokinetic parameters of each dose group in the single-dose test of Comparative Example 4 in healthy subjects

[0097]

Claims

1. A gastric retentive double-layer sustained-release tablet, characterized in that: The invention comprises two drug release layers, namely, a quick-release layer and a sustained-release layer; the quick-release layer comprises an active ingredient, 3-[4-[4-(1H-benzotriazole-1-yl)butyl]piperazine-1-yl]benzisothiazole hydrochloride, a filler I and a disintegrant; the sustained-release layer comprises an active ingredient, 3-[4-[4-(1H-benzotriazole-1-yl)butyl]piperazine-1-yl]benzisothiazole hydrochloride, a filler II, an expansion material, a release retardant, an expansion promoter and a stabilizer.

2. A gastric retentive double-layer sustained-release tablet according to claim 1, characterized in that: The quick-release layer filler I is one or more of microcrystalline cellulose, lactose, and starch, and its content is 8%-35% of the total weight of the gastric retentive double-layer sustained-release tablet; the quick-release layer disintegrant is one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and sodium carboxymethyl starch, and its content is 0.3%-3% of the total weight of the gastric retentive double-layer sustained-release tablet.

3. The gastric retentive double-layer sustained-release tablet according to claim 1, characterized in that: The sustained-release layer filler II is one or more of microcrystalline cellulose, lactose, starch, and pregelatinized starch, and its content is 5%-35% of the total weight of the gastric retention double-layer sustained-release tablet.

4. The gastric retentive double-layer sustained-release tablet according to claim 1, characterized in that: The expansion material of the sustained-release layer is polyethylene oxide, and its content is 8%-50% of the total weight of the gastric retention double-layer sustained-release tablet; the molecular weight of polyethylene oxide is 1×10 6 Up to 7×10 6 .

5. The gastric retentive double-layer sustained-release tablet according to claim 1, characterized in that: The release retardant of the sustained-release layer is one or more of hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K15M, hydroxypropyl methylcellulose K100M, hydroxypropyl methylcellulose K100LV, ethyl cellulose, carbomer, and methacrylic acid-methyl methacrylate copolymer, and its content is 0%-30% of the total weight of the gastric retention double-layer sustained-release tablet.

6. The gastric retentive double-layer sustained-release tablet according to claim 1, characterized in that: The expansion promoter of the sustained-release layer is one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch, and the content thereof is 13%-35% of the total weight of the gastric retention double-layer sustained-release tablet.

7. The gastric retentive double-layer sustained-release tablet according to claim 1, characterized in that: The sustained-release layer stabilizer is one or more of butylated hydroxytoluene, propyl gallate, ascorbic acid, anhydrous citric acid, tartaric acid, sodium pyrosulfite, and disodium edetate, and its content is 0%-5% of the total weight of the gastric retention double-layer sustained-release tablet.

8. The gastric retentive double-layer sustained-release tablet according to claim 1, characterized in that: The gastric retentive double-layer sustained-release tablet further comprises a lubricant, which is one or more of talc, stearic acid, magnesium stearate, and colloidal silicon dioxide, and its content is 0.01%-2% of the total weight of the gastric retentive double-layer sustained-release tablet; it also comprises coating ingredients, such as polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, and acrylic resin.

9. A method for preparing a gastric retentive double-layer sustained-release tablet according to any one of claims 1 to 8, characterized in that: The following steps are involved: Preparation of immediate-release granules: Mix the immediate-release layer raw materials and auxiliary materials except the lubricant uniformly, use a dry granulator to perform dry granulation, add the lubricant and mix uniformly to obtain the immediate-release layer mixed powder; Preparation of sustained-release granules: Mix the raw materials and auxiliary materials of the sustained-release layer except the lubricant uniformly, perform dry granulation using a dry granulator, add the lubricant and mix uniformly to obtain a mixed powder of the sustained-release layer; Tablet compression: First, lightly compress the sustained-release layer granules into loose tablets, then add the immediate-release layer granules and press into shape to obtain gastric retentive double-layer sustained-release tablets.

10. Use of the gastric retentive double-layer sustained-release tablet according to any one of claims 1 to 8 in the preparation of therapeutic drugs for hypertension, pulmonary hypertension and benign prostatic hyperplasia.

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