Gastroretentive double-layer sustained-release tablet, preparation method therefor, and use thereof

Abstract

Disclosed are a gastroretentive double-layer sustained-release tablet, a preparation method therefor, and use thereof. An active ingredient of the gastroretentive double-layer sustained-release tablet is 3-[4-[4-(lH-benzotriazol-1-yl)butyl]piperazin-1-yl]benzisothiazole hydrochloride. Said tablet consists of two drug release layers comprising an immediate-release layer and a sustained-release layer. The immediate-release layer comprises the active ingredient, a filler I, and a disintegrant, and the sustained-release layer comprises the active ingredient, a filler II, a swelling material, a release blocker, a swelling enhancer, and a stabilizer. Said tablet can prolong the in vivo absorption window of the drug, maintain the plasma concentration, and prolong the in vivo half-life of the active ingredient.

Description

A gastric retention bilayer sustained-release tablet, its preparation method and application Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations and relates to a gastric retention bilayer sustained-release tablet, its preparation method, and its application. Background Technology

[0002] 3-[4-[4-(1H-benzotriazol-1-yl)butyl]piperazin-1-yl]benzisothiazole hydrochloride can antagonize 5-HT 2A Receptors, while blocking α 1A It also acts as a calcium channel blocker. Pharmacological studies have shown that it has good therapeutic effects on diseases such as hypertension, pulmonary hypertension, and benign prostatic hyperplasia (CN103833658A, application number 202411785128.3). However, pharmacokinetic studies show that this compound has a short half-life in both animals and humans, and the plasma drug concentration drops significantly after 12 hours. Therefore, multiple daily doses are needed to maintain the blood drug concentration, which will cause great inconvenience to patients.

[0003] Experimental studies have shown that the absorption of this compound in the gastrointestinal tract is uneven, with weak absorption in the intestines, resulting in a short absorption window in vivo. Conventional bilayer sustained-release tablets and multi-unit granules, after slow release in vivo, cannot maintain sustained absorption for a long period, making it difficult to achieve once-daily dosing (QD). This makes the development of sustained-release tablets that can be administered QD a technical challenge. Summary of the Invention

[0004] The technical problem to be solved by this invention is to address the above-mentioned shortcomings by designing, researching, and providing a gastric retention bilayer sustained-release tablet containing 3-[4-[4-(1H-benzotriazol-1-yl)butyl]piperazin-1-yl]benzisothiazole hydrochloride (code name MT-1207), its preparation method, and its application. This gastric retention bilayer sustained-release tablet, after oral administration, can fully absorb gastric juice and swell to form a hydrogel. This not only controls the drug release rate, but the water-absorbing and swelling hydrogel formulation can produce a gastric retention effect through the combined effects of flocculation, mucosal adhesion, and expansion volume. It exhibits a sustained release effect of more than 16 hours in both in vivo and in vitro, and good absorption in Beagle dogs, enabling once-daily dosing and increasing patient compliance. Furthermore, this gastric retention sustained-release tablet is prepared using a dry granulation process, which is simple and conducive to industrial production.

[0005] The gastric retention bilayer sustained-release tablet of the present invention comprises two drug release layers: an immediate-release layer and a sustained-release layer. The immediate-release layer contains the active ingredient 3-[4-[4-(1H-benzotriazol-1-yl)butyl]piperazin-1-yl]benzisothiazole hydrochloride (code name MT-1207), filler I, and a disintegrant; the sustained-release layer contains the active ingredient 3-[4-[4-(1H-benzotriazol-1-yl)butyl]piperazin-1-yl]benzisothiazole hydrochloride (code name MT-1207), filler II, a bulking material, a release inhibitor, a bulking promoter, and a stabilizer.

[0006] The gastric retention bilayer sustained-release tablet of the present invention, wherein the immediate-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 retention bilayer sustained-release tablet.

[0007] The gastric retention bilayer sustained-release tablet of the present invention contains a rapid-release layer disintegrant that is one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch, and the content of which is 0.3%-3% of the total weight of the gastric retention bilayer sustained-release tablet.

[0008] The gastric retention bilayer 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 retention bilayer sustained-release tablet.

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

[0010] The polyoxyethylene described in this invention has a molecular weight of 1×10⁻⁶. 6 Up to 7×10 6 .

[0011] The gastric retention bilayer sustained-release tablet of the present invention contains a release inhibitor in the sustained-release layer that is one or more of hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K15M, hydroxypropyl methylcellulose K100M, hydroxypropyl methylcellulose K100LV, ethyl cellulose, carbomer, and methyl methacrylate copolymer, the content of which is 0%-30% of the total weight of the gastric retention bilayer sustained-release tablet.

[0012] The gastric retention bilayer sustained-release tablet of the present invention contains a sustained-release layer swelling promoter that is one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch, and its content is 13%-35% of the total weight of the gastric retention bilayer sustained-release tablet.

[0013] The gastric retention bilayer sustained-release tablet of the present invention contains a sustained-release layer stabilizer that is one or more of butylated hydroxytoluene, propyl gallate, ascorbic acid, anhydrous citric acid, tartaric acid, sodium metabisulfite, and disodium edetate, and the content of the stabilizer is 0%-5% of the total weight of the gastric retention bilayer sustained-release tablet.

[0014] The gastric retention bilayer sustained-release tablet of the present invention further comprises a lubricant, wherein the lubricant is one or more of talc, stearic acid, magnesium stearate, and colloidal silica, and its content is 0.01%-2% of the total weight of the gastric retention bilayer sustained-release tablet.

[0015] The gastric retention bilayer sustained-release tablet of the present invention may also contain coating components, such as polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, and acrylic resin.

[0016] The preparation method of the gastric retention bilayer sustained-release tablet of the present invention includes the following steps:

[0017] Preparation of instant-release granules: Mix the instant-release layer raw materials and auxiliary materials (excluding lubricant) evenly, perform dry granulation using a dry granulator, add lubricant and mix evenly to obtain instant-release layer mixed powder.

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

[0019] Tableting: First, lightly compress the sustained-release granules into loose tablets, then add the immediate-release granules and compress to form a bilayer sustained-release tablet for gastric retention.

[0020] The application of the gastric retention double-layer sustained-release tablet disclosed in this invention in the preparation of drugs for the treatment of diseases such as hypertension, pulmonary hypertension, and benign prostatic hyperplasia.

[0021] The beneficial effects of this invention are:

[0022] This invention relates to a gastric retention bilayer sustained-release tablet. The immediate-release layer rapidly releases the drug to achieve an effective blood concentration, while the sustained-release layer expands, prolonging the tablet's residence time in the stomach and thus extending the drug's absorption window in vivo to maintain blood concentration. This significantly prolongs the in vivo half-life of MT-1207, reducing the frequency of dosing and increasing patient compliance. The preparation process is simple, suitable for industrial production, and has broad development prospects. Attached Figure Description

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

[0024] Figure 2 shows the dissolution curves of the products from Examples 5-8.

[0025] Figure 3 shows the dissolution curves of the products from Examples 9-10, 12 and Comparative Examples 1-3.

[0026] Figure 4 shows the plasma drug concentration curves for Examples 9-10 and Comparative Examples 1-3.

[0027] Figure 5. Blood concentration curve of MT-1207 active pharmaceutical ingredient in dogs after oral administration.

[0028] Figure 6 shows the blood drug concentration curves in a single-dose trial in healthy subjects for Comparative Example 4. Detailed Implementation

[0029] The following examples illustrate the technical solutions of the present invention. These examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the following examples.

[0030] Examples 1-4: Preparation of MT-1207 immediate-release tablets

[0031] MT-1207 immediate-release tablets were prepared according to the components and their contents listed in Table 1 below. The preparation process is as follows:

[0032] Mix the raw and auxiliary materials (excluding lubricant) for 15 minutes, then perform dry granulation using a dry granulator. Add the lubricant and mix for 5 minutes to obtain an immediate-release mixed powder, which can then be compressed into tablets.

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

[0034] Powder flowability test method: The bulk density and tap density of the particles are tested using a graduated cylinder and a tap density tester, respectively, and the Karl index is calculated.

[0035] The particle size distribution was tested using a laser particle size analyzer with a dry method at a dispersion pressure of 1.5 bar.

[0036] Take this product and perform the dissolution and release assay according to the method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), using hydrochloric acid at pH 1.0 as the medium and a rotation speed of 75 rpm. Samples were taken at 5, 10, 15, 30, 45, and 60 minutes, and the cumulative dissolution rate was calculated. The results are shown in Table 2, and the dissolution curve is shown in Figure 1.

[0037] Table 2. Cumulative dissolution and particle characterization results of Examples 1-4

[0038] As shown in Table 2, the immediate-release granules prepared in Examples 1-4 have good flowability, and the tablets can be rapidly dissolved in acidic media, which provides a guarantee for the rapid release of MT-1207 gastric retention bilayer sustained-release tablets in the early stage.

[0039] Examples 5-8: Preparation of MT-1207 sustained-release tablets

[0040] MT-1207 sustained-release tablets were prepared according to the ingredients and their contents listed in Table 3 below. The preparation process is as follows:

[0041] Mix the raw and auxiliary materials (excluding lubricant) for 15 minutes, then perform dry granulation using a dry granulator. Add the lubricant and mix for 5 minutes to obtain a slow-release layer mixed powder, which can then be compressed into tablets.

[0042] Table 3. Prescription composition of Examples 5-8

[0043] Powder flowability test method: The bulk density and tap density of the particles are tested using a graduated cylinder and a tap density tester, respectively, and the Karl index is calculated.

[0044] Take this product and perform dissolution and release assays according to the method described in Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II. The apparatus used was a self-made sedimentation basket, with pH 4.0 ABS solution as the medium, and a rotation speed of 75 rpm. Samples were taken at 1, 2, 4, 6, 8, 12, 16, and 24 hours to test and calculate the cumulative dissolution rate. Using a dissolution apparatus with 900 mL of 37℃ pH 4.0 ABS solution as the medium, the expansion size was measured at different time points, and the expansion rate was calculated. The results are shown in Table 4, and the dissolution curve is shown in Figure 2.

[0045] Expansion rate = (Volume after expansion / Initial volume) * 100%;

[0046] Volume = Major axis * Minor axis * Thickness (Volume is only a rough calculation).

[0047] Table 4. Cumulative dissolution and swelling rate data for Examples 5-8

[0048] As shown in Table 4, Examples 5-8 can all achieve slow and continuous release within 24 hours, and the expansion performance is good, maintaining an expansion rate of over 160% within 6 hours.

[0049] Stabilizer evaluation test:

[0050] The sustained-release layer mixture powder prepared in Example 8 was mixed with different stabilizers in a certain proportion, and then placed in open containers or bottles at 40°C and 75% RH to examine the changes in content and related substances. The results showed that each stabilizer had a different degree of stabilizing effect on the sustained-release layer mixture powder.

[0051] Table 5 Results of Stabilizer Investigation

[0052] Examples 9-12: Preparation of MT-1207 Gastric Retention Bilayer Sustained-Release Tablets

[0053] The MT-1207 gastric retention bilayer sustained-release tablets were prepared according to the ingredients and their contents listed in Table 6 below. The preparation process is as follows:

[0054] Mix the raw and auxiliary materials, excluding the lubricant, for 15 minutes, then perform dry granulation using a dry granulator. Add the lubricant and mix for 5 minutes to obtain a mixture of immediate-release and slow-release powders, which are then compressed into tablets using a double-layer tablet press.

[0055] Comparative Example 1: Preparation of Conventional MT-1207 Bilayer Sustained-Release Tablets

[0056] The MT-1207 conventional double-layer sustained-release tablets were prepared according to the ingredients and their contents listed in Table 6 below. The preparation process is as follows:

[0057] Mix the raw and auxiliary materials, excluding the lubricant, for 15 minutes, then perform dry granulation using a dry granulator. Add the lubricant and mix for 5 minutes to obtain a mixture of immediate-release and slow-release powders, which are then compressed into tablets using a double-layer tablet press.

[0058] Table 6. Prescription composition of Examples 9-12 and Comparative Example 1

[0059] Comparative Examples 2-3: Preparation of Enteric-Coated MT-1207 Granules

[0060] According to the ingredients and their contents listed in Table 7 below, fluidized bed microcapsule loading and coating were performed. Tartaric acid cores were loaded with the drug and coated with an isolation layer to obtain immediate-release cores. MT-1207 sustained-release cores with different coating weight-gain were prepared from these immediate-release cores. The immediate-release cores and the sustained-release cores with different coating weight-gain were then packaged into enteric-coated gelatin capsules as shown in the table, with each capsule containing 60 mg of MT-1207.

[0061] Table 7. Prescription composition of Comparative Examples 2-3

[0062] *Film coating premix (gastric-soluble type): Purchased from Shanghai Carrefour Coating Technology Co., Ltd., model number Obadai 03K19229-CN transparent.

[0063] Take this product and, according to the Dissolution and Release Determination Method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), conduct a two-stage media release test on MT-1207 enteric-coated granules 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 retention double-layer sustained-release tablets are tested for release using pH 4.0 ABS solution as the medium. The rotation speed is 75 rpm, and the cumulative dissolution rate is calculated. Using a dissolution apparatus, with 900 mL of 37℃ pH 4.0 ABS solution as the medium, the expansion size of the gastric retention double-layer sustained-release tablets is measured at different time points, and the expansion rate is calculated. The results are shown in Tables 8 and 9, and the dissolution curve is shown in Figure 3.

[0064] Table 8. Expansion rate data for Examples 9-12

[0065] Table 9. Cumulative dissolution data for Examples 9, 10, 12 and Comparative Examples 1-3

[0066] As shown in Tables 8 and 9, the gastric retention bilayer sustained-release tablets prepared in Examples 9-12 can achieve slow and continuous release within 24 hours, and all exhibit good expansion performance.

[0067] Beagel dog PK test:

[0068] Examples 9-10 are gastric retention bilayer sustained-release tablets. Comparative Example 1 is a conventional bilayer sustained-release tablet. A postprandial test was conducted, with the drug administered 30 minutes after the administration of an equal amount of food. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, 10, 12, 16, 20, and 24 hours to measure plasma drug concentration. Comparative Examples 2-3 are enteric-coated granules. A fasting test was conducted, with overnight fasting. Pentagastrin was administered before drug administration, and food was given 4 hours after drug administration. Blood samples were collected at 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours to measure plasma drug concentration. The drug was administered in equal numbers of male and female samples. Pharmacokinetic parameters are shown in Table 10, and plasma drug concentrations are shown in Figure 4.

[0069] The results showed that conventional bilayer sustained-release tablets and enteric-coated granules reached peak blood drug concentrations in about 1 to 3 hours, after which the concentrations rapidly decreased, and no significant absorption was observed after 8 hours. The blood drug concentrations of gastric retention bilayer 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 efficacy and more stable blood drug concentrations.

[0070] Table 10. Dog pk test results of Examples 9-10 and Comparative Examples 1-3

[0071] A canine pharmacokinetics (PK) test was conducted using MT-1207 active pharmaceutical ingredient. Dogs were fasted for 12 hours prior to the experiment. Blood samples were collected at 5 min, 10 min, 15 min, 30 min, 1, 2, 4, 6, 8, 12, and 24 h after oral administration to measure plasma drug concentration. Eight dogs (half male and half female) were included. Results showed a significant decrease in plasma drug concentration after 12 h (see Figure 5).

[0072] Comparative Example 4: Preparation of MT-1207 Immediate-Release Tablets

[0073] MT-1207 immediate-release tablets were prepared using wet granulation and tableting processes, according to the components and their contents listed in Table 11 below.

[0074] Healthy volunteers were selected and administered single oral doses of 5 mg, 10 mg, 20 mg, and 40 mg immediate-release tablets after an overnight fast. Blood samples were collected at 5 min, 10 min, 15 min, 30 min, 1, 1.5, 2, 4, 6, 8, 12, 24, 24, and 48 h to measure plasma drug concentrations. Results showed that plasma drug concentrations decreased significantly after 12 h. Pharmacokinetics are shown in Table 12, and plasma drug concentrations are shown in Figure 6.

[0075] 1) Research Subjects

[0076] 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) 2 Body mass index (BMI) between 18 and 28 kg / m² 2 (3) The subject (including the partner) is willing to take effective contraceptive measures from the time of screening to 6 months after the last administration of the study drug; (4) The physical examination and vital signs are normal or abnormal and have no clinical significance.

[0077] Exclusion criteria: (1) Smoking more than 5 cigarettes per day for 3 months prior to the test; (2) Allergic constitution (multiple drug and food allergies); (3) History of drug use and / or alcohol abuse (consuming 14 units of alcohol per week: 1 unit = 285 mL of beer, or 25 mL of spirits, or 100 mL of wine); (4) Donating blood or experiencing significant blood loss (>450 mL) within 3 months prior to the screening; (5) Taking any drugs that alter liver enzyme activity within 28 days prior to the screening; (6) Taking any prescription drugs, over-the-counter drugs, any vitamin products, or herbal remedies within 14 days prior to the screening; (7) Consuming a special diet (including...) within 2 weeks prior to the screening. (7) Those who consume dragon fruit, mango, grapefruit, etc., or engage in strenuous exercise, or other factors that affect drug absorption, distribution, metabolism, and excretion; (8) Those who have CYP3A4, P-gp, or Bcrp inhibitors or inducers, such as itraconazole, ketoconazole, or dronedarone; (9) Those who have recently undergone significant changes in their diet or exercise habits; (10) Those who have taken the study drug or participated in a drug clinical trial within three months prior to taking the study drug; (11) Those who have a history of dysphagia or any gastrointestinal disease that affects drug absorption; (12) Those who have any disease that increases the risk of bleeding, such as hemorrhoids, acute gastritis, or gastric and duodenal ulcers. (13) Clinically significant ECG abnormalities, QTC>450ms; (14) Sitting systolic blood pressure below 100mmHg, and / or sitting diastolic blood pressure below 60mmHg; (15) Orthostatic hypotension during screening; (16) History of orthostatic hypotension or syncope; (17) Female subjects who are breastfeeding or have a positive serum pregnancy result during the screening period or trial; (18) Clinically significant abnormalities in clinical laboratory tests, or other clinical findings within 12 months prior to screening showing the following diseases (including but not limited to gastrointestinal, kidney, liver, nerve, blood, endocrine, tumor, etc.). (19) Positive screening results for viral hepatitis (including hepatitis B and hepatitis C), HIV antibody, or Treponema pallidum antibody; (20) Acute illness or concomitant medication occurring from the screening stage to the time of study drug administration; (21) Consumption of chocolate, any caffeinated or xanthine-rich food or beverage within 48 hours prior to taking the study drug; (22) Consumption of any alcoholic beverage within 48 hours prior to taking the study drug; (23) Positive urine drug screening results or a history of drug abuse or drug use within the past five years; (24) Subjects deemed unsuitable for participation in this trial by the investigator.

[0078] 2) Statistical processing

[0079] The AUC was calculated using Phoenix WinNonlin software (version 7.0 and above) and the non-compartmental model method. 0-t AUC 0- ∞ C max Key pharmacokinetic parameters, etc.

[0080] 3) Safety evaluation

[0081] During the trial, subjects underwent the following safety checks: vital signs (respiration and temperature, systolic and diastolic blood pressure), 12-lead electrocardiogram, orthostatic hypotension, cardiac monitoring, laboratory tests (blood biochemistry, routine blood and urine tests), symptoms and physical examination, and were assessed throughout the course of medication and followed up on adverse drug events.

[0082] Table 11. Formulation of immediate-release tablets in Comparative Example 4

[0083] Table 12 Summary of pharmacokinetic parameters for each dose group in the single-dose trial in healthy subjects in Comparative Example 4

Claims

1. A gastric retention bilayer sustained-release tablet, characterized in that, It contains two drug release layers: an immediate-release layer and a sustained-release layer. The immediate-release layer contains the active ingredient 3-[4-[4-(1H-benzotriazol-1-yl)butyl]piperazin-1-yl]benzisothiazole hydrochloride, filler I, and a disintegrant. The sustained-release layer contains the active ingredient 3-[4-[4-(1H-benzotriazol-1-yl)butyl]piperazin-1-yl]benzisothiazole hydrochloride, filler II, a swelling material, a release inhibitor, a swelling promoter, and a stabilizer.

2. The gastric retention bilayer sustained-release tablet according to claim 1, characterized in that, The immediate-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 retention bilayer sustained-release tablet; the immediate-release layer disintegrant is one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch, and its content is 0.3%-3% of the total weight of the gastric retention bilayer sustained-release tablet.

3. The gastric retention bilayer 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 bilayer sustained-release tablet.

4. The gastric retention bilayer sustained-release tablet according to claim 1, characterized in that, The sustained-release layer expansion material is polyethylene oxide, with a content of 8%-50% of the total weight of the gastric retention bilayer sustained-release tablets; the molecular weight of polyethylene oxide is 1×10⁻⁶. 6 Up to 7×10 6 .

5. The gastric retention bilayer sustained-release tablet according to claim 1, characterized in that, The release inhibitor 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 methyl methacrylate copolymer, and its content is 0%-30% of the total weight of the gastric retention bilayer sustained-release tablet.

6. The gastric retention bilayer sustained-release tablet according to claim 1, characterized in that, The sustained-release layer swelling promoter is one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch, and its content is 13%-35% of the total weight of the gastric retention bilayer sustained-release tablet.

7. The gastric retention bilayer 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 metabisulfite, and disodium edetate, and its content is 0%-5% of the total weight of the gastric retention bilayer sustained-release tablet.

8. The gastric retention bilayer sustained-release tablet according to claim 1, characterized in that, The aforementioned gastric retention bilayer sustained-release tablet further comprises a lubricant, which is one or more of talc, stearic acid, magnesium stearate, and colloidal silica, and its content is 0.01%-2% of the total weight of the gastric retention bilayer sustained-release tablet; it also comprises a coating component, such as polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, and acrylic resin.

9. A method for preparing a gastric retention bilayer sustained-release tablet according to any one of claims 1-8, characterized in that, Includes the following steps: Preparation of immediate-release granules: Mix the immediate-release layer raw materials and auxiliary materials (excluding lubricant) evenly, perform dry granulation using a dry granulator, add lubricant and mix evenly to obtain immediate-release layer mixed powder; Preparation of sustained-release granules: Mix the raw and auxiliary materials of the sustained-release layer, except for the lubricant, evenly, and perform dry granulation using a dry granulator. Add the lubricant and mix evenly to obtain the sustained-release layer mixed powder. Tableting: First, lightly compress the sustained-release granules into loose tablets, then add the immediate-release granules and compress to form a bilayer sustained-release tablet for gastric retention.

10. The use of the gastric retention double-layer sustained-release tablet according to any one of claims 1-8 in the preparation of a drug for the treatment of hypertension, pulmonary hypertension, and benign prostatic hyperplasia.

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