Single-layer osmotic pump controlled release tablet for sinus node If channel inhibitor and preparation method of single-layer osmotic pump controlled release tablet

Abstract

The invention discloses a sinus node If channel inhibitor single-layer osmotic pump controlled release tablet and a preparation method thereof. The sinoatrial node If channel inhibitor single-layer osmotic pump controlled release tablet comprises a tablet core and a semi-permeable coating film wrapping the tablet core, and small drug release holes are formed in the semi-permeable coating film; the tablet core comprises a sinus node If channel inhibitor, a suspending aid, an adhesive, a filler and a lubricant; the sinus node If channel inhibitor is ivabradine or a pharmaceutical salt thereof. In order to solve the problem that the plasma concentration fluctuates violently due to the fact that the ivabradine hydrochloride tablet releases medicine too fast, the single-layer osmotic pump controlled release tablet is prepared, and compared with the ivabradine hydrochloride tablet, the single-layer osmotic pump controlled release tablet has the advantages that Tmax is obviously prolonged, the slow release effect is obvious, Cmax is reduced, the plasma concentration fluctuates little, and remarkable clinical benefits are achieved.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and particularly relates to a sinoatrial node I f Channel inhibitor monolayer osmotic pump controlled-release tablet and preparation method thereof. Background Art

[0002] Heart failure is a complex syndrome caused by abnormal cardiac structure or function, which leads to ventricular contraction or filling disorders. It often occurs in the elderly, and the prevalence and incidence increase with the patient's age. Many clinical studies have shown that an increase in resting heart rate and increased myocardial oxygen consumption will directly or indirectly increase the incidence of cardiovascular diseases including heart failure, the rate of re-hospitalization, and the risk of death. Lowering the resting heart rate can alleviate complications, improve prognosis, and reduce the risk of death in patients. A variety of drugs that act on heart rate, represented by beta-blockers, have been widely used in clinical practice, but there are still certain limitations.

[0003] Ivabradine is the first f Current-specific blockers that reduce I f The current amplitude and the slope of diastolic depolarization of the sinus node can improve the prognosis of heart failure by simply slowing down the heart rate, without affecting intracardiac conduction, ventricular repolarization, and myocardial contractility. It can be widely used in patients who are prohibited from or restricted from using beta-blockers. Ivabradine hydrochloride tablets were first developed by Servier, France, and launched in 2006. They are used for chronic stable angina pectoris and NYHA II to IV chronic heart failure in adults with coronary heart disease with a heart rate ≥ 70 beats / minute. They can be used in combination with standard treatment including beta-blockers, and for patients who are contraindicated or cannot tolerate beta-blockers.

[0004] The most common adverse reactions in clinical use of ivabradine hydrochloride tablets are bradycardia and phosphenes. 3.3% of patients reported bradycardia, and 0.5% had severe bradycardia (≤40 beats / minute). Bradycardia is related to the dramatic blood concentration fluctuations of immediate-release tablets. Patent CN116983272A discloses an ivabradine hydrochloride sustained-release tablet, which selects a mixed hydrophilic gel skeleton material to achieve a sustained-release effect; compared with ivabradine hydrochloride tablets, the ivabradine hydrochloride sustained-release tablet provided by the patent has a drug T in Beagle dogs after oral administration. max It is about 1 hour after taking the medicine, the peak time is relatively fast, and the sustained-release effect is not significant. Summary of the invention

[0005] One of the purposes of the present invention is to provide a sinoatrial node f A channel inhibitor single-layer osmotic pump controlled-release tablet comprises a tablet core and a semipermeable coating wrapped around the tablet core, wherein the semipermeable coating is provided with drug-releasing holes;

[0006] The core comprises, by weight percentage: sinoatrial node I f Channel inhibitor 5% to 30%, suspending agent 3% to 20%, adhesive 1% to 10%, filler 30% to 90%, lubricant 0.1% to 3%;

[0007] The sinoatrial node I f The channel inhibitor is ivabradine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt may be a pharmaceutically acceptable salt such as sulfate or hydrochloride;

[0008] The suspending agent is one or a combination of hydroxypropyl methylcellulose, sodium carboxymethyl cellulose or hydroxypropyl cellulose.

[0009] Preferably, in the present invention, the weight average molecular weight of the hypromellose in the suspending agent is 164,000 to 1,000,000.

[0010] Further, the semipermeable coating is one of the following combinations:

[0011] (1) Controlled release coating layer

[0012] (2) Combination of an inner controlled release coating layer and an outer film coating layer.

[0013] Furthermore, the weight gain of the controlled release coating layer is 5% to 9%, and the weight gain of the film coating layer is 2% to 12%.

[0014] Furthermore, the controlled release coating layer comprises, by weight percentage: 50% to 80% of film-forming material and 20% to 50% of pore-forming agent.

[0015] Furthermore, in the tablet core, the binder is one or a combination of corn starch, polyvinyl pyrrolidone, polyvinyl alcohol or hydroxypropyl cellulose, the filler is one or a combination of microcrystalline cellulose, sorbitol, mannitol, lactose, and the lubricant is one or a combination of magnesium stearate, talc, magnesium lauryl sulfate, micro-powdered silica gel or polyethylene glycol.

[0016] Furthermore, in the controlled release coating layer, the film-forming material is one or a combination of ethyl cellulose, hydroxypropyl methylcellulose, cellulose acetate or acrylic resin, and the pore-forming agent is one or a combination of polyethylene glycol, methyl cellulose or hydroxypropyl methylcellulose; in the film coating layer, the film coating film-forming material is one or a combination of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol or methyl cellulose.

[0017] Furthermore, the diameter of the drug-releasing pores is 0.4 mm to 1.0 mm.

[0018] The second object of the present invention is to provide the above-mentioned sinoatrial node I fThe preparation method of the channel inhibitor monolayer osmotic pump controlled-release tablet comprises the following steps:

[0019] Step 1: Sinus node I f The channel inhibitor, suspending agent, binder and filler are mixed, a wetting agent is added to prepare a soft material, wet granulation is performed, and the granules are dried to a moisture content of 2% to 4%, and dry granulation is performed; a lubricant is added to mix; and tableting is performed to obtain a tablet core.

[0020] Step 2, preparing a coating solution for a semipermeable coating film, and coating the tablet core with the coating solution to obtain the single-layer osmotic pump controlled-release tablet.

[0021] Furthermore, in step 1, the wetting agent is anhydrous ethanol, water or ethanol solution.

[0022] In one embodiment of the present invention, anhydrous ethanol is used as a wetting agent for granulation.

[0023] Specifically, for the controlled release coating layer, the film-forming material and the pore-forming agent are added to the coating solvent to obtain a controlled release coating solution, and the tablet cores are placed in a coating pan for coating and aging; for the thin film coating layer, the film coating film-forming material and water are made into a thin film coating solution, and the tablets after the controlled release coating are placed in a coating pan for coating.

[0024] Furthermore, for the controlled release coating solution, the coating solvent can be selected from one or a combination of acetone, acetone-water solution, dichloromethane-isopropanol, and dichloromethane.

[0025] Furthermore, the film-forming material for the film coating can be any commercially available product without any specific requirement. In one embodiment of the present invention, the film-forming material for the film coating is a film coating premix.

[0026] Aiming at the problem that the ivabradine hydrochloride tablets release too quickly and cause the blood drug concentration to fluctuate violently, the present invention is designed to release the sinoatrial node f The channel inhibitor (ivabradine or its pharmaceutical salt) is prepared into a monolayer osmotic pump controlled release tablet to achieve the technical effect of slow and stable release and stable fluctuation of blood drug concentration. In the previous experiments of the inventor, the commonly used suspending agent polyoxyethylene (PEO) of osmotic pump controlled release tablets was investigated. The results showed that for the specific drug ivabradine, when PEO was used as a suspending agent, it was exposed to high temperature of 60°C for 30 days, and the related substances increased rapidly, and the stability of the preparation was relatively poor. Therefore, the present invention selects hydroxypropyl methylcellulose as a suspending agent.

[0027] Compared with ivabradine hydrochloride tablets, the monolayer osmotic pump controlled release tablets T max Significantly prolonged, sustained release effect, C maxThe drug concentration in the blood fluctuates less, which has significant clinical benefits. The selection of cellulose materials as suspending agents, combined with semipermeable membrane coating technology, can reduce the impact of the pH environment of the gastrointestinal tract on the tablet core and increase the stability of the preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The release results of the preparations of Examples 1 and 2 are shown below.

[0029] Figure 2 The release results of the preparations of Examples 2-5 are shown below.

[0030] Figure 3 The pharmacokinetic results of the preparation of Example 2 and ivabradine hydrochloride tablets are shown in FIG. DETAILED DESCRIPTION

[0031] The preferred embodiments of the present invention will be described in detail below in conjunction with examples. It should be understood that the following examples are provided only for the purpose of illustration and are not intended to limit the scope of the present invention. Those skilled in the art may make various modifications and substitutions to the present invention without departing from the purpose and spirit of the present invention.

[0032] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0033] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0034] In the following examples, the hydroxypropyl methylcellulose used in the tablet core is hydroxypropyl methylcellulose K4M, the polyvinyl pyrrolidone is polyvinyl pyrrolidone K30, the cellulose acetate used in the controlled release layer coating is cellulose acetate CA-398-10, and the polyethylene glycol is polyethylene glycol 3350.

[0035] Examples 1-5

[0036] The prescription compositions of Examples 1-5 are shown in Table 1.

[0037] Table 1 Prescription composition of Examples 1-5

[0038]

[0039] The preparation process of the preparations in Examples 1-5 comprises the following steps:

[0040] 1. Tablet core preparation: Weigh ivabradine hydrochloride, polyoxyethylene or hydroxypropyl methylcellulose, polyvinyl pyrrolidone, and lactose, and mix them evenly. Add wetting agent anhydrous ethanol to granulate, wet granulate, dry until the moisture content of the granules reaches 2-4%, and granulate. Add lubricant magnesium stearate and mix. Press into round tablets with a diameter of 8 mm to obtain the tablet core.

[0041] 2. Preparation of osmotic pump controlled-release tablets: Take acetone and purified water in a ratio of 95:5 to prepare an acetone aqueous solution, add cellulose acetate and polyethylene glycol and stir until completely dissolved to obtain a coating solution for a semipermeable coating membrane. The tablet core is placed in a coating pan, the tablet bed temperature is controlled at 20-25°C, and the coating weight gain is 5-7%. After coating, age at 40°C for 12 hours. Use a laser puncher to punch a drug release hole with a diameter of about 0.4-1.0 mm on the semipermeable membrane at the center of one side of the osmotic pump to obtain ivabradine hydrochloride osmotic pump controlled-release tablets.

[0042] Test Example 1

[0043] By weight, 1 part of ivabradine hydrochloride was mixed with 5 parts of polyoxyethylene and 5 parts of hydroxypropyl methylcellulose, and then exposed to a high temperature of 60°C for 30 days to investigate the compatibility of raw and auxiliary materials. The relevant substances were determined according to the import registration standard for ivabradine hydrochloride tablets. The results are shown in Table 2.

[0044] Table 2 Compatibility test results of raw materials and auxiliary materials (related substances, %)

[0045]

[0046] The tablets prepared in Example 1 and Example 2 were exposed to a high temperature of 60° C. for 30 days to investigate the influencing factors. The related substances were determined according to the import registration standard for ivabradine hydrochloride tablets. The results are shown in Table 3.

[0047] Table 3 Stability test results (related substances, %)

[0048]

[0049] According to the above results, at a high temperature of 60°C, the impurities in the preparation made of hypromellose increase slowly and the stability is relatively high, so hypromellose is selected as the suspending agent in the present invention.

[0050] Test Example 2

[0051] According to the second method of dissolution and release determination method 0931 of the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia, the tablets prepared in Example 1 and Example 2 were subjected to an in vitro dissolution test, and the peak area was determined by the external standard method of the high performance liquid chromatograph. The chromatographic conditions for the determination were hexadecylamino bonded silica gel as the column filler, phosphate buffer (4.54g of potassium dihydrogen phosphate, 1000ml of water to dissolve, and 85% phosphoric acid to adjust the pH value to 3.0) - acetonitrile (88:12) as the mobile phase, the detection wavelength was 220nm, the column temperature was 40°C, and the flow rate was 1.6ml / min. The cumulative release percentage was calculated by the external standard method, and the results are shown in Figure 1 .

[0052] Depend on Figure 1It can be seen that the release rate of the preparation made of polyoxyethylene is faster than the release rate of the preparation made of hypromellose.

[0053] Test Example 3

[0054] According to the second method of dissolution and release determination method in Part IV of the Chinese Pharmacopoeia 2020, the tablets prepared in Example 2-5 were subjected to an in vitro dissolution test, the peak area was determined by the external standard method of high performance liquid chromatography, and the cumulative release percentage was calculated by the external standard method. The results are shown in Figure 2 .

[0055] The dosage of pore-forming agent can significantly adjust the release rate. The release rate increases with the increase of the dosage of pore-forming agent. When the dosage of pore-forming agent is 20% or 30%, the cumulative release percentage of the drug in 2h can reach 20% to 40%, the cumulative release percentage of the drug in 4h can reach 40% to 70%, and the cumulative release percentage of the drug in 24h can reach not less than 90%.

[0056] Test Example 4

[0057] The tablets prepared in Example 2 were film coated, and the film coating process was as follows: the film coating premix and purified water were taken and stirred to form a uniform coating solution with a solid content of 12%; the coating composition was placed in a coating pan, the tablet bed temperature was controlled at 43-47°C, and the coating weight gain was 3-5%. Then, the tablets were used together with ivabradine hydrochloride tablets (Servier, France, 5 mg, 3 tablets) for in vivo pharmacokinetic study in beagle dogs.

[0058] Depend on Figure 3 The results show that, compared with the immediate-release tablets, the peak time of the monolayer osmotic pump preparation prepared by the present invention is about 4 hours after oral administration, T max Significantly longer than that of patent CN116983272 (peak time is about 1 hour after oral administration), C max It is significantly reduced, the sustained-release effect is obvious, and the blood drug concentration fluctuates smoothly.

Claims

1. A sinoatrial node I f A channel inhibitor monolayer osmotic pump controlled-release tablet comprises a tablet core and a semipermeable coating wrapped around the tablet core, wherein drug-releasing holes are provided on the semipermeable coating, and the tablet core comprises a semipermeable coating, wherein: The core comprises, by weight percentage: sinoatrial node I f Channel inhibitor 5% to 30%, suspending agent 3% to 20%, adhesive 1% to 10%, filler 30% to 90%, lubricant 0.1% to 3%; the sum of the weight percentages of all raw materials is 100%; The sinoatrial node I f The channel inhibitor is ivabradine or a pharmaceutically acceptable salt thereof; The suspending agent is one or a combination of hydroxypropyl methylcellulose, sodium carboxymethyl cellulose or hydroxypropyl cellulose.

2. The sinoatrial node according to claim 1 f The channel inhibitor monolayer osmotic pump controlled-release tablet is characterized in that: The semipermeable coating is one of the following: (i) controlled release coating layer; Or (ii) the inner layer is a controlled release coating layer and the outer layer is a film coating layer.

3. The sinoatrial node according to claim 2 f The channel inhibitor monolayer osmotic pump controlled-release tablet is characterized in that: The weight gain of the controlled release coating layer is 5% to 9%, and the weight gain of the film coating layer is 2% to 12%.

4. The sinoatrial node according to claim 2 f The channel inhibitor monolayer osmotic pump controlled-release tablet is characterized in that: The controlled release coating layer comprises, by weight percentage, 50% to 80% of film-forming material and 20% to 50% of pore-forming agent.

5. The sinoatrial node according to claim 2 f The channel inhibitor monolayer osmotic pump controlled-release tablet is characterized in that: In the tablet core, the binder is one or a combination of corn starch, polyvinyl pyrrolidone, polyvinyl alcohol or hydroxypropyl cellulose, the filler is one or a combination of microcrystalline cellulose, sorbitol, mannitol, lactose, and the lubricant is one or a combination of magnesium stearate, talc, magnesium lauryl sulfate, micro powder silica gel or polyethylene glycol.

6. The sinoatrial node according to claim 2 f The channel inhibitor monolayer osmotic pump controlled-release tablet is characterized in that: In the controlled release coating layer, the film-forming material is one or a combination of ethyl cellulose, hydroxypropyl methylcellulose, cellulose acetate or acrylic resin, and the pore-forming agent is one or a combination of polyethylene glycol, methyl cellulose or hydroxypropyl methylcellulose; in the film coating layer, the film-forming material is one or a combination of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol or methyl cellulose.

7. The sinoatrial node according to claim 1 f The channel inhibitor monolayer osmotic pump controlled-release tablet is characterized in that: The diameter of the drug-releasing pores is 0.4 mm to 1.0 mm.

8. The sinoatrial node I according to any one of claims 1 to 7 f The method for preparing a channel inhibitor monolayer osmotic pump controlled-release tablet is characterized in that: The following steps are involved: Step 1: Sinus node I f The channel inhibitor, suspending agent, binder and filler are mixed, a wetting agent is added to prepare a soft material, wet granulation is performed, and the granules are dried to a moisture content of 2% to 4%, and dry granulation is performed; a lubricant is added to mix; and tableting is performed to obtain a tablet core; Step 2, preparing a coating solution for a semipermeable coating film, and coating the tablet core with the coating solution to obtain the single-layer osmotic pump controlled-release tablet.

9. The preparation method according to claim 8, characterized in that: In step 1, the wetting agent is anhydrous ethanol, water or ethanol solution.

10. The preparation method according to claim 8, characterized in that: For the controlled coating layer, the film-forming material and the pore-forming agent are added to the coating solvent to obtain a controlled-release coating solution, and the tablet cores are placed in a coating pan for coating; for the thin-film coating layer, the film-forming material and water are mixed to obtain a thin-film coating solution, and the tablets after the controlled-release coating are placed in a coating pan for coating.

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