Ivabradine hydrochloride sustained-release tablet and preparation method therefor

Abstract

An ivabradine hydrochloride sustained-release tablet and a preparation method therefor. The sustained-release tablet contains ivabradine hydrochloride, a gel matrix sustained-release material, a pore-forming agent and a lubricant, wherein the gel matrix sustained-release material is two hydroxypropyl methylcellulose having different viscosities, the pore-forming agent is selected from one or a mixture of two of microcrystalline cellulose and lactose, and the lubricant is selected from one or a mixture of several of colloidal silicon dioxide and magnesium stearate. The sustained-release tablet only requires oral administration once a day, such that the peak-valley concentration fluctuation can be reduced, the drug taking frequency of a patient can be reduced, and the drug compliance of the patient can be improved.

Description

Ivabradine hydrochloride sustained-release tablets and preparation method thereof Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to an ivabradine hydrochloride sustained-release tablet and a preparation method thereof. Background Art

[0002] Ischemic heart disease remains a major cause of global health loss, with the incidence of angina pectoris increasing annually worldwide. Stable angina is the most common symptom in patients with stable coronary artery disease. Due to recurrent myocardial ischemia, angina symptoms can severely limit patients' daily activity and endurance, significantly negatively impacting their quality of life.

[0003] Heart rate is the primary factor influencing myocardial oxygen consumption. An increased heart rate shortens the cardiac cycle, thereby reducing systolic perfusion and further decreasing myocardial oxygen supply. Disturbances in myocardial oxygen consumption can lead to myocardial ischemia, which in turn induces angina symptoms. Abnormal heart rate is an independent risk factor for cardiovascular disease. An increased resting heart rate is positively correlated with mortality from cardiovascular events such as coronary heart disease, heart failure (HF), and myocardial infarction. Therefore, controlling resting heart rate has become a primary target for the clinical treatment of cardiovascular disease.

[0004] Ivabradine hydrochloride, chemical name 7,8-dimethoxy-3-(3-[[(1S)(4,5-dimethoxybenzocyclobutan-1-yl)methyl]-methylamino]propyl)-1,3,4,5-tetrahydro-2-hydro-benzazepin-2-one hydrochloride, CAS registration number 148849-67-6, its structural formula is shown below:

[0005] Ivabradine hydrochloride is the first pacemaker current inhibitor with a specific effect of lowering heart rate. Ivabradine hydrochloride works by blocking the IF current in the sinoatrial node, which controls cardiac contraction and regulates heart rate. When the IF current is blocked, the heart rate decreases, reducing the pressure on the heart. It is mainly used clinically for patients with chronic heart failure (NYHA class II to IV) with sinus rhythm and a heart rate ≥75 beats / min, accompanied by cardiac systolic dysfunction, in combination with standard treatment (including beta-blockers), or for patients who are contraindicated or cannot tolerate beta-blocker treatment. The currently marketed dosage form of ivabradine hydrochloride is tablets with specifications of 5mg and 7.5mg, which are taken orally twice a day, in the morning and evening with meals. It is currently available in the United States, Japan, Europe, and other countries.

[0006] Nearly 45,000 patients have participated in clinical studies of ivabradine hydrochloride tablets. The most common adverse reactions are photopsia (phosphenes) and bradycardia, which are dose-dependent. Bradycardia was reported in 3.3% of patients, with 0.5% experiencing severe bradycardia (≤40 beats / min) in the first 2 to 3 months of treatment. This is primarily due to the rapid peak in plasma concentration of ivabradine hydrochloride tablets after oral administration, which leads to a rapid decrease in heart rate and large fluctuations in plasma concentrations. Therefore, the development of a once-daily sustained-release formulation of ivabradine hydrochloride is of great significance for reducing troughs in plasma concentrations, reducing adverse reactions, and improving medication compliance.

[0007] Patent CN1482901A discloses a solid pharmaceutical composition for controlled release of ivabradine, which is prepared by mixing two polymethacrylates The mixture of RS and ivabradine hydrochloride is heated to 80-130°C to prepare a sustained-release mixture, and the drug release rate is adjusted by changing the ratio of the two polymers. This method is complex in preparation and is not easy to industrialize.

[0008] Patent CN102908327A discloses a sustained-release preparation of ivabradine or a pharmaceutically acceptable salt thereof, wherein the sustained-release matrix material is selected from one or a mixture of polyoxyethylene, polyvinyl acetate, and polyvinyl pyrrolidone polymers. The sustained-release tablets prepared using hydroxypropyl methylcellulose K100M can only achieve an 8-hour sustained-release. High-molecular-weight polyoxyethylene (molecular weight greater than 1,000,000 Daltons) is used as the sustained-release material, ivabradine bisulfate is used as the active ingredient, and another water-insoluble waxy matrix material, glyceryl behenate, is added to achieve a sustained-release effect. Furthermore, compared to the immediate-release tablets, after oral administration to Beagle dogs, the peak concentration was reduced by approximately 75%, which can easily lead to problems of too low peak concentration and poor efficacy. In addition, the invention changes the salt form of ivabradine, and its effect on the pharmacological activity of the compound in vivo is also unpredictable.

[0009] Summary of the Invention

[0010] The purpose of this section is to summarize some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of this application to avoid obscuring the purpose of this section, the abstract and the title of the invention, and such simplifications or omissions should not be used to limit the scope of the present invention.

[0011] In view of the above problems and / or the problems existing in the prior art, the present invention is proposed.

[0012] Therefore, the purpose of the present invention is to overcome the deficiencies in the prior art and provide an ivabradine hydrochloride sustained-release tablet, characterized in that it comprises:

[0013] Ivabradine hydrochloride, gel matrix sustained-release material, pore-forming agent and lubricant;

[0014] Among them, the mass parts of raw materials are:

[0015] The gel skeleton sustained-release material is hydroxypropyl methylcellulose, which is selected from a mixture of two hydroxypropyl methylcelluloses with viscosity indication values ​​of 100,000 mPa·s and 5 mPa·s, respectively. The weight ratio of 100,000 mPa·s hydroxypropyl methylcellulose to 5 mPa·s hydroxypropyl methylcellulose is 3:1 to 1:4.

[0016] As a preferred embodiment of the ivabradine hydrochloride sustained-release tablets of the present invention, the weight ratio of the 100,000 mPa·s hypromellose to the 5 mPa·s hypromellose is 1:2 to 1:3.

[0017] As a preferred embodiment of the ivabradine hydrochloride sustained-release tablets of the present invention, the weight ratio of the gel skeleton sustained-release material in the sustained-release tablets is 40-70%.

[0018] As a preferred embodiment of the ivabradine hydrochloride sustained-release tablets of the present invention, the weight ratio of the gel skeleton sustained-release material in the sustained-release tablets is 50% to 60%.

[0019] As a preferred embodiment of the ivabradine hydrochloride sustained-release tablets of the present invention, the pore-forming agent is selected from microcrystalline cellulose and lactose, or a mixture of the two.

[0020] As a preferred embodiment of the ivabradine hydrochloride sustained-release tablets of the present invention, the pore-forming agent is a mixture of microcrystalline cellulose and lactose, wherein the weight ratio of the microcrystalline cellulose in the sustained-release tablet is 0% to 33%, and the weight ratio of the lactose in the sustained-release tablet is 0% to 33%.

[0021] As a preferred embodiment of the ivabradine hydrochloride sustained-release tablets of the present invention, the weight ratio of the microcrystalline cellulose in the sustained-release tablets is 8% to 25%, and the weight ratio of the lactose in the sustained-release tablets is 8% to 25%.

[0022] As a preferred embodiment of the ivabradine hydrochloride sustained-release tablets of the present invention, the lubricant is selected from colloidal silicon dioxide, magnesium stearate, or a mixture of the two.

[0023] As a preferred embodiment of the ivabradine hydrochloride sustained-release tablets of the present invention, the method comprises the following steps: preliminarily mixing ivabradine hydrochloride with a porogenic material, and then mixing with a gel matrix material; then adding a lubricant for final mixing, and tableting to obtain ivabradine hydrochloride sustained-release tablets.

[0024] Beneficial effects of the present invention:

[0025] The present invention screens a series of sustained-release matrix materials and finds that a mixture of hydroxypropyl methylcellulose with different molecular weights is used as the sustained-release matrix material, and a mixture of microcrystalline cellulose and lactose is used as a pore-forming agent. Ivabradine hydrochloride sustained-release tablets with a sustained release of 24 hours can be prepared by a conventional direct powder tableting method. The process is simple and easy to industrialize. The sustained-release effect in vivo is obvious, and multiple doses are unnecessary. When taken once a day, the peak concentration is reduced to about 50% of that of an immediate-release tablet, while still ensuring the pharmacological effect in vivo. Furthermore, the salt form of ivabradine is not changed. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. Those skilled in the art can also derive other drawings based on these drawings without inventive effort. Among them:

[0027] Figure 1 is a comparison of the dissolution curves of Comparative Examples 1 and 2 and Examples 15, 21, 30, and 33;

[0028] FIG2 is a graph showing the mean plasma concentration-time curve of ivabradine after oral administration of 5 mg of Example 30 and ivabradine hydrochloride tablets (2.5 mg / time, BID) to beagle dogs;

[0029] FIG3 is a graph showing the mean plasma concentration-time curve of ivabradine in beagle dogs after oral administration of 10 mg of Example 21 and ivabradine hydrochloride tablets (5 mg / time, BID);

[0030] FIG4 is a graph showing the mean plasma concentration-time curve of ivabradine in beagle dogs after oral administration of 15 mg of Example 33 and ivabradine hydrochloride tablets (7.5 mg / time, BID);

[0031] Figure 5 is a graph showing the average blood concentration-time curve of the ivabradine sustained-release preparation in patent CN102908327A. DETAILED DESCRIPTION

[0032] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0033] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0034] Secondly, the term "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in various places throughout this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive of other embodiments.

[0035] Examples 1 to 6

[0036] Comparison of sustained-release materials:

[0037] Sustained-release tablets were prepared according to the ingredients and amounts shown in Table 1. The amounts in Table 1 represent the weight (mg) of each component in each tablet. For each example, the raw materials and excipients were mixed uniformly and then compressed into tablets weighing approximately 200 mg using a tablet press. The formulation is shown in Table 1.

[0038] Table 1 Note 1: The active ingredient is dosed in the form of hydrochloride.

[0039] According to the first method (basket method) of the 0931 dissolution and release determination method of the Chinese Pharmacopoeia 2020 edition, the tablets prepared in Examples 1 to 6 were subjected to dissolution experiments. 900 ml of purified water was used as the dissolution medium, and the dissolution experiment was carried out at 37 ± 0.5 ° C and a speed of 75 rpm. Small samples were taken from the dissolution medium at 1, 2, 4, 6, 8, 12, 16, and 24 hours respectively. Each sample was tested with a high performance liquid chromatograph (HPLC, detection wavelength: 220 nm) to calculate the release rate. The results are shown in Table 2.

[0040] Table 2

[0041] Table 2 shows that the samples using polyethylene oxide, Kollidon SR, and glyceryl behenate as the sustained-release matrix (Examples 1, 2, and 6) had a slow dissolution rate and were not completely dissolved after 24 hours. After 24 hours of dissolution and release, the tablet using HPMC K100M alone as the sustained-release material (Example 3) still had drug residue inside the core, indicating incomplete release and unsatisfactory sustained-release effect. After 4 hours of dissolution and release, the tablet using HPMC E5 alone as the sustained-release material (Example 4) had no flakes in the dissolution cup and failed to produce a significant sustained-release effect. Using a mixture of HPMC K100M and HPMC E5 as the sustained-release matrix material (Example 5), a sustained-release preparation with good sustained-release effect can be prepared using a powder direct compression process. Compared with the prescription granules in patent CN102908327A, the prescription granules have better fluidity and compressibility, and no sticking occurs during the tableting process.

[0042] Examples 7 to 11

[0043] Comparison of porogen types and dosages:

[0044] Sustained-release tablets were prepared according to the ingredients and amounts shown in Table 3. The amounts in Table 3 represent the weight (mg) of each component in each tablet. For each example, the raw materials and excipients were mixed uniformly and then compressed into tablets weighing approximately 200 mg using a tablet press. The formulation is shown in Table 3.

[0045] Table 3 Note 1: The active ingredient is dosed in the form of hydrochloride.

[0046] According to the first method (basket method) of the 0931 dissolution and release determination method of the Chinese Pharmacopoeia 2020 edition, the tablets prepared in Examples 7 to 11 were subjected to dissolution experiments. 900 ml of purified water was used as the dissolution medium, and the dissolution experiment was carried out at 37 ± 0.5 ° C and a speed of 75 rpm. Small samples were taken from the dissolution medium at 1, 2, 4, 6, 8, 12, 16, and 24 hours respectively. Each sample was tested with a high performance liquid chromatograph (HPLC, detection wavelength: 220 nm) to calculate the release rate. The results are shown in Table 4.

[0047] Table 4

[0048] Table 4 shows that a 1:1 mixture of microcrystalline cellulose and lactose as pore-forming agents can be used to prepare a sustained-release preparation (Example 10) with good sustained-release effect using a powder direct compression process. The granules of this prescription have good fluidity and compressibility.

[0049] Examples 12 to 22

[0050] Comparison of sustained-release material dosage and proportion:

[0051] Sustained-release tablets were prepared according to the ingredients and amounts shown in Tables 5 to 6. The amounts in Tables 5 to 6 represent the weight (mg) of each component in each tablet. For each example, the raw materials and excipients were mixed uniformly and then compressed into tablets weighing approximately 200 mg using a tablet press. The formulations are shown in Tables 5 to 6.

[0052] Table 5 Note 1: The active ingredient is dosed in the form of hydrochloride.

[0053] Table 6 Note 1: The active ingredient is dosed in the form of hydrochloride.

[0054] According to the first method (basket method) of the 0931 dissolution and release determination method of the Chinese Pharmacopoeia 2020 edition, the tablets prepared in Examples 12 to 22 were subjected to dissolution experiments. 900 ml of purified water was used as the dissolution medium, and the dissolution experiment was carried out at 37 ± 0.5 ° C and a speed of 75 rpm. Small samples were taken from the dissolution medium at 1, 2, 4, 6, 8, 12, 16, and 24 hours respectively. Each sample was tested with a high performance liquid chromatograph (HPLC, detection wavelength: 220 nm) to calculate the release rate. The results are shown in Table 7.

[0055] Table 7

[0056] As can be seen from Table 7, when the total amount of hypromellose is between 50% and 60% and the ratio of HPMC K100M:HPMC E5 is between 1:2 and 1:3 (Examples 15, 16, 20, and 21), an ivabradine formulation with good sustained-release effect can be prepared by the powder direct compression process, and has an in vitro release characteristic of less than 35% of the active ingredient (i.e., ivabradine) released within 1 hour, 50% to 80% released within 4 to 6 hours (cumulative release), and more than 85% released within 12 hours (cumulative release).

[0057] Examples 23 to 27

[0058] Comparison of lubricant dosage and ratio:

[0059] Sustained-release tablets were prepared according to the ingredients and amounts shown in Table 8. The amounts in Table 8 represent the weight (mg) of each component in each tablet. For each example, the raw materials and excipients were mixed uniformly and then compressed into tablets weighing approximately 200 mg using a tablet press. The formulation is shown in Table 8.

[0060] Table 8 Note 1: The active ingredient is dosed in the form of hydrochloride.

[0061] The tableting force and sample hardness during the tableting process of Examples 21, 23 to 27 were monitored in real time. The monitoring results are shown in Table 9.

[0062] Table 9

[0063] For the samples of Examples 21, 23 to 27, 10 pieces were taken and the content was tested respectively. The test results are shown in Table 10.

[0064] Table 10

[0065] The powder properties of the granules of Examples 21, 23 to 27 were tested using an intelligent powder tester. The test results are shown in Table 11.

[0066] Table 11

[0067] According to the test results in Tables 9 to 11, it can be seen that when the total amount of lubricant is 2% to 3% (Examples 21, 23, and 24), the prescribed granules have good fluidity and compressibility, making the ivabradine sustained-release preparation meet the requirements of the preparation process of the present invention.

[0068] Examples 28 to 33

[0069] Comparison of active substance dosage:

[0070] Sustained-release tablets were prepared according to the ingredients and amounts shown in Table 12. The amounts in Table 12 represent the weight (mg) of each component in each tablet. For each example, the raw materials and excipients were mixed uniformly and then compressed into tablets weighing approximately 200 mg using a tablet press. The formulation is shown in Table 12.

[0071] Table 12 Note 1: The active ingredient is dosed in the form of hydrochloride.

[0072] According to the first method (basket method) of the 0931 dissolution and release determination method of the Chinese Pharmacopoeia 2020 edition, the tablets prepared in Examples 28 to 33 were subjected to dissolution experiments. 900 ml of purified water was used as the dissolution medium, and the dissolution experiment was carried out at 37 ± 0.5 ° C and a speed of 75 rpm. Small samples were taken from the dissolution medium at 1, 2, 4, 6, 8, 12, 16, and 24 hours respectively. Each sample was tested with a high performance liquid chromatograph (HPLC, detection wavelength: 220 nm) to calculate the release rate. The results are shown in Table 13.

[0073] Table 13

[0074] Table 13 shows that when HPMC K100M and HPMC E5 are mixed in a ratio of 1:3 as the sustained-release matrix material, 5 mg and 15 mg of active substance are used, and the powder direct compression process can be used to prepare ivabradine formulations with good sustained-release effects.

[0075] Comparative Examples 1-2

[0076] Ivabradine hydrochloride sustained-release tablets were prepared by direct powder compression as described in patent CN102908327A.

[0077] Prescription see Table 14

[0078] Table 14 Note 1: The active ingredient is dosed in the form of hydrochloride.

[0079] Preparation method:

[0080] After the raw materials and excipients were uniformly mixed, they were directly compressed to produce sustained-release tablets. By reproducing the patented preparation method, simply mixing the raw materials and excipients resulted in poor granular flowability. Due to the excessive amount of fine powder and the limited variety of excipients, the tablets had low hardness and poor compressibility during the tableting process, accompanied by sticking. The release rate of the sustained-release tablets in 900 ml of aqueous medium was measured using high-performance liquid chromatography (HPLC, detection wavelength: 220 nm). The results are shown in Table 15.

[0081] Table 15

[0082] Table 15 shows that the ivabradine hydrochloride sustained-release tablets prepared according to the method of patent CN102908327A have a sustained-release effect, achieving a sustained release of 16 to 24 hours. The dissolution curves of Comparative Examples 1 and 2 and Examples 15, 21, 30, and 33 are compared in Figure 1.

[0083] As can be seen from Figure 1, the early dissolution rates of Examples 15, 21, 30, and 33 are all faster than those of Comparative Examples 1 and 2, indicating that the drug can be released faster in the body and the effective therapeutic concentration can be quickly reached.

[0084] Powder science testing:

[0085] The powder properties of the granules of Comparative Examples 1 and 2 and Examples 10, 13, 16, and 21 were tested using an intelligent powder tester. The test results are shown in Table 16.

[0086] Table 16

[0087] According to Table 16, it can be seen that the flowability of the particles of Examples 10, 13, 16, and 21 is better than that of the sample particles of Comparative Examples 1 and 2.

[0088] Stability test:

[0089] The products of Comparative Examples 1 and 2 and Examples 16, 21, 30 and 33 were packaged in aluminum bags and placed at 40°C / RH75% for 1 month, 3 months and 6 months, and at 25°C / RH60% for 1 month, 3 months, 6 months and 12 months, for stability investigation. The results are shown in Tables 17 to 18.

[0090] Table 17

[0091] Table 18

[0092] According to Tables 17 and 18, it can be seen that the samples prepared using the prescription in patent CN102908327A (Comparative Examples 1 and 2) showed a significant increase in the content of related substances in the stability experiment, while the samples prepared using the prescriptions in Examples 16, 21, 30, and 33 of the sustained-release preparation of the present invention showed only a slight increase in the content of related substances under the conditions of 40°C / RH75%, and almost no increase under the conditions of 25°C / RH60%, and the stability was significantly better than that of the prescription in patent CN102908327A.

[0093] Pharmacokinetic studies:

[0094] The samples prepared by the prescriptions of Examples 21, 30 and 33 and the commercial preparation of ivabradine hydrochloride rapid-release tablets (produced by Servier, France, trade name: Corant ) conducted a comparative pharmacokinetic study in beagle dogs, using a 5 mg dose of Break it into two 2.5mg half tablets, take them 12h apart, and compare them with one tablet of Example 30 (containing ivabradine 5mg); Taken 12 hours apart, the results were compared with those of Example 21 (containing ivabradine 10 mg); the 7.5 mg specification tablet was taken Each time, the dose was taken 12 hours apart, and a comparative study was conducted with one tablet of the sample of Example 33 (containing 15 mg of ivabradine). The experimental results are shown in Figures 2 to 4.

[0095] According to the results of Figures 2 to 5, it can be seen that the sustained-release preparation prepared by the present invention reduces Cmax compared to the immediate-release preparation, but is still higher than that of patent CN102908327A. It can not only overcome the side effect of Cmax rising too fast after taking the immediate-release preparation, resulting in a too fast drop in heart rate, but also ensure that an effective therapeutic concentration is reached. The ivabradine sustained-release preparation prepared by the present invention reaches a peak time of about 1 hour after taking the medicine, and can achieve a 24-hour long-term sustained release, while the sustained-release preparation in patent CN102908327A reaches a peak time of about 4 hours after taking the medicine, and can only achieve a 12-hour sustained release. Therefore, the ivabradine sustained-release preparation prepared by the present invention is faster in onset and has a longer sustained release time than the sustained-release preparation in patent CN102908327A, and is comprehensively superior to the sustained-release preparation in patent CN102908327A.

[0096] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. An ivabradine hydrochloride sustained-release tablet, characterized in that: include, Ivabradine hydrochloride, gel matrix sustained-release material, pore-forming agent and lubricant; Among them, the mass fraction of raw materials is: The gel skeleton sustained-release material is hydroxypropyl methylcellulose, which is selected from a mixture of two hydroxypropyl methylcelluloses with viscosity indication values ​​of 100,000 mPa·s and 5 mPa·s, respectively, and the weight ratio of 100,000 mPa·s hydroxypropyl methylcellulose to 5 mPa·s hydroxypropyl methylcellulose is 3:1 to 1:

4.

2. The ivabradine hydrochloride sustained-release tablet according to claim 1, characterized in that: The weight ratio of the 100000 mPa·s hydroxypropyl methylcellulose to the 5 mPa·s hydroxypropyl methylcellulose is 1:2 to 1:

3.

3. The ivabradine hydrochloride sustained-release tablet according to claim 1 or 2, characterized in that: The weight ratio of the gel skeleton sustained-release material in the sustained-release tablet is 40-70%.

4. The ivabradine hydrochloride sustained-release tablet according to claim 3, characterized in that: The weight ratio of the gel skeleton sustained-release material in the sustained-release tablet is 50% to 60%.

5. The ivabradine hydrochloride sustained-release tablet according to claim 1 or 2, characterized in that: The pore-forming agent is selected from microcrystalline cellulose and lactose or a mixture of the two.

6. The ivabradine hydrochloride sustained-release tablet according to claim 5, characterized in that: The pore-forming agent is a mixture of microcrystalline cellulose and lactose, wherein the weight ratio of the microcrystalline cellulose in the sustained-release tablet is 0% to 33%, and the weight ratio of the lactose in the sustained-release tablet is 0% to 33%.

7. The ivabradine hydrochloride sustained-release tablet according to claim 6, characterized in that: The weight ratio of the microcrystalline cellulose in the sustained-release tablet is 8% to 25%, and the weight ratio of the lactose in the sustained-release tablet is 8% to 25%.

8. The ivabradine hydrochloride sustained-release tablet according to any one of claims 1, 2, 4, 6, and 7, characterized in that: The lubricant is selected from colloidal silicon dioxide, magnesium stearate or a mixture of the two.

9. The method for preparing the ivabradine hydrochloride sustained-release tablets according to any one of claims 1 to 8, characterized in that: include, Ivabradine hydrochloride is preliminarily mixed with the pore-forming material and then mixed with the gel skeleton material; a lubricant is then added for final mixing and tableting is performed to obtain ivabradine hydrochloride sustained-release tablets.

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