Eplerenone and dapagliflozin compound sustained release tablet and preparation method thereof

Abstract

The invention discloses an eplerenone and dapagliflozin compound sustained-release tablet and a preparation method thereof. The eplerenone and dapagliflozin compound sustained-release tablet sequentially comprises a drug-containing pill core, a sustained-release coating layer, a tabletting auxiliary material layer and a coating layer from inside to outside, the drug-containing pellet core is prepared from a first filling agent, dapagliflozin propylene glycol monohydrate, eplerenone and an adhesive; the adhesive is formed by combining hydroxypropyl methylcellulose E3 or hydroxypropyl methylcellulose E5 with hydroxypropyl methylcellulose K4M; the sustained-release coating layer comprises a sustained-release coating material, a pore-foaming agent and a solubilizer; the tabletting auxiliary material layer comprises a second filling agent, a flow aid, a disintegrating agent and a lubricating agent; the disintegrating agent is prepared from low-substituted hydroxy propyl cellulose and cross-linked sodium carboxymethyl cellulose. According to the eplerenone and dapagliflozin compound sustained release tablet prepared by the invention, the content of dapagliflozin is uniform, the dissolution curve of eplerenone and dapagliflozin is completely released within 24 hours, meanwhile, the problems of layering and cracking of tablets during tabletting are solved, and the product stability is improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an eplerenone-dapagliflozin compound sustained-release tablet and a preparation method thereof. Background Art

[0002] Eplerenone (Eplerenone, I) is a new generation of selective aldosterone antagonists (MRA drugs) developed by Pfizer / Pharmacia. It selectively acts on mineralocorticoid receptors and blocks their binding to aldosterone, and does not act on androgen and progesterone receptors. Aldosterone is a component of the renin-angiotensin-aldosterone system (RAAS). Aldosterone binds to mineralocorticoid receptors in epithelial tissues (such as kidneys) and non-epithelial tissues (such as heart, blood vessels and brain), and increases blood pressure by inducing sodium reabsorption and possible other mechanisms. Eplerenone can improve the quality of life of patients with left ventricular dysfunction (ejection fraction ≤ 40%). Clinical trials have shown that this product can also be used for congestive heart failure after acute myocardial infarction, alone or in combination with other antihypertensive drugs for the treatment of hypertension.

[0003] Dapagliflozin (FarxigaTM) is a new type of anti-diabetic drug jointly developed by Bristol-Myers Squibb and AstraZeneca. It is an SGLT2 inhibitor (sodium-glucose co-transporter 2 inhibitor) with good safety and tolerability, as well as kidney protection, diuresis and hyperkalemia reduction. It has been approved for the treatment of heart failure in diabetic patients. Studies have found that the combination of MRA drugs and SGLT2 inhibitors is safe and may reduce potassium retention caused by MRA and reduce the rate of hospitalization due to heart failure, especially for HFpEF (heart failure with preserved ejection fraction) patients. In addition, it can also reduce the risk of hyperkalemia and reduce the interruption of MRA treatment due to hyperkalemia.

[0004] Currently, no relevant literature has been found to disclose the sustained-release preparation of the eplerenone-dapagliflozin compound and the related preparation process. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the deficiencies and defects mentioned in the above background technology and provide an eplerenone-dapagliflozin compound sustained-release tablet and a preparation method thereof.

[0006] In order to solve the above technical problems, the technical solution proposed by the present invention is: An eplerenone-dapagliflozin compound sustained-release tablet, comprising, from the inside to the outside, a pill core, a sustained-release coating layer, a tabletting auxiliary material layer and a coating layer; The pill core includes a first filler, dapagliflozin propylene glycol monohydrate, eplerenone and a binder; the binder is a combination of hypromellose E3 or hypromellose E5 and hypromellose K4M; The sustained-release coating layer comprises a sustained-release coating material, a pore-forming agent and a solubilizing agent; The tableting auxiliary material layer comprises a second filler, a glidant, a disintegrant and a lubricant; the disintegrant consists of low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose.

[0007] As a further improvement, the pill core includes, by weight, 80 to 120 parts of a first filler, 5.5 to 13.5 parts of dapagliflozin propylene glycol monohydrate, 20 to 55 parts of eplerenone, and 9 to 12 parts of a binder.

[0008] As a further improvement, the binder is hypromellose E3 or hypromellose E5, and is composed of hypromellose K4M in a mass ratio of 1:(1.8~2.2).

[0009] As a further improvement, the sustained-release coating layer includes 5 to 10 parts of sustained-release coating material, 1 to 2 parts of pore-forming agent, and 4 to 6 parts of solubilizer, by weight.

[0010] As a further improvement, the sustained-release coating material is one or more combinations of ethyl cellulose aqueous dispersion, cellulose acetate phthalate, or hydroxypropyl cellulose acrylate copolymer.

[0011] As a further improvement, the tableting auxiliary material layer includes, by weight, 10 to 20 parts of a second filler, 7 to 15 parts of a disintegrant, 0.5 to 1 part of a lubricant, and 0.5 to 1 part of a glidant.

[0012] As a further improvement, the disintegrant is composed of low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose in a mass ratio of 1:(0.8~1.2).

[0013] As a further improvement, the coating layer comprises a film coating premix.

[0014] The present invention also provides a method for preparing the eplerenone-dapagliflozin compound sustained-release tablets, comprising the following steps: S1. Mix hydroxypropyl methylcellulose E3 or E5 with hydroxypropyl methylcellulose K4M to prepare a binder solution, and then add dapagliflozin raw materials and mix well; S2. The first filler and the eplerenone raw material are dry mixed, and then the solution obtained in S1 is added for granulation; S3. The solubilizer, pore-forming agent, and sustained-release coating material are added to water to prepare a suspension solution; S4. After the granulated material in S2 is dried, the suspension solution obtained in S3 is sprayed into the granulation and dried; S5. A glidant is added to the material obtained in S4, and then a disintegrant, a second filler and a lubricant are added, mixed and tableted to obtain a sustained-release tablet; S6. Film-coating the sustained-release tablets prepared in S5 to obtain the eplerenone-dapagliflozin compound sustained-release tablets.

[0015] Compared with the prior art, the present invention has the following beneficial effects: The present invention improves components such as adhesives, sustained-release coating materials, disintegrants, and the like, and improves the process, so that the dapagliflozin content in the eplerenone-dapagliflozin compound sustained-release tablets is uniform, and the dissolution curves of eplerenone and dapagliflozin reach complete release within 24 hours, while solving the problems of tablet compression delamination and tablet splitting, and improving product stability.

[0016] Compared with the single-drug dapagliflozin tablets and single-drug eplerenone currently on the market, this compound sustained-release tablet can alleviate the potassium retention problem caused by the use of eplerenone, reduce the hospitalization rate due to heart failure, reduce the drug resistance of single medication, and reduce the number of times patients take medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0018] Figure 1 This is the dissolution curve of dapagliflozin in hydrochloric acid medium at pH = 1.2; Figure 2 This is the dissolution curve of dapagliflozin in hydrochloric acid medium at pH = 4.5; Figure 3 This is the dissolution curve of dapagliflozin in hydrochloric acid medium at pH = 6.8; Figure 4 This is the dissolution curve of eplerenone in hydrochloric acid medium at pH = 1.2; Figure 5 This is the dissolution curve of eplerenone in hydrochloric acid medium at pH = 4.5; Figure 6 This is the dissolution curve of eplerenone in hydrochloric acid medium at pH = 6.8. DETAILED DESCRIPTION

[0019] In order to facilitate the understanding of the present invention, the present invention will be described more comprehensively and carefully in combination with preferred embodiments below, but the protection scope of the present invention is not limited to the following specific embodiments.

[0020] Unless otherwise defined, all professional terms used below have the same meanings as those generally understood by those skilled in the art. The professional terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of protection of the present invention.

[0021] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0022] In some specific embodiments, the eplerenone dapagliflozin compound sustained-release tablets of the present invention sequentially comprise, from the inside to the outside, a pill core, a sustained-release coating layer, a tabletting auxiliary material layer and a coating layer.

[0023] Contains pill core In some embodiments, the pill core comprises a first filler, dapagliflozin propylene glycol monohydrate, eplerenone and a binder. Specifically, by weight, the pill core comprises 80 to 120 parts of the first filler (filler 1), 5.5 to 13.5 parts of dapagliflozin propylene glycol monohydrate, 20 to 55 parts of eplerenone, and 9 to 12 parts of a binder.

[0024] In some embodiments, the first filler includes any one or more combinations of lactose, microcrystalline cellulose, corn starch, and mannitol.

[0025] In some embodiments, the binder is hydroxypropyl methylcellulose E3 or hydroxypropyl methylcellulose E5, which is mixed with hydroxypropyl methylcellulose K4M in a mass ratio of 1: (1.8~2.2) (preferably 1: 2). When only one type of hydroxypropyl methylcellulose (E3 or E5) is used as a binder, the release of the dissolution curves of eplerenone and dapagliflozin are completely released before 24 hours, while when only hydroxypropyl methylcellulose (K4M) is used as a binder, the dissolution curves of eplerenone and dapagliflozin cannot reach complete release at 24 hours. The present invention can be completely released just in 24 hours, so that patients only need to take the medicine once a day. Since different binders have different effects on different drugs, the present invention can simultaneously achieve qualified dissolution rates of two APIs, eplerenone and dapagliflozin.

[0026] Sustained release coating In some embodiments, the sustained-release coating layer comprises a sustained-release coating material (slow-release skeleton), a pore-forming agent and a solubilizer. Specifically, by weight, the sustained-release coating layer comprises 5 to 10 parts of the sustained-release coating material, 1 to 2 parts of the pore-forming agent, and 4 to 6 parts of the solubilizer.

[0027] In some embodiments, the sustained-release coating material is one or more combinations of ethylcellulose aqueous dispersion, cellulose acetate phthalate, and hydroxypropyl cellulose acrylate copolymer. The specific sustained-release coating material of the present invention can improve the bioavailability of dapagliflozin and eplerenone and make the drug release slower and more stable. Excessive use of sustained-release coating material leads to incomplete drug dissolution, and complete release cannot be achieved within 24 hours. Too little use cannot achieve a sustained-release effect, and complete release occurs before 24 hours.

[0028] In some embodiments, the solubilizer includes one or more combinations of sodium dodecyl sulfate and Tween 80. The porogen includes one or more combinations of polyethylene glycol 1400, 1500, and 600.

[0029] Tableting auxiliary material layer In some embodiments, the tableting auxiliary material layer includes a second filler (filler 2), a glidant, a disintegrant, and a lubricant. Specifically, by weight, the tableting auxiliary material layer includes 10 to 20 parts of the second filler, 7 to 15 parts of the disintegrant, 0.5 to 1 part of the lubricant, and 0.5 to 1 part of the glidant.

[0030] In some embodiments, the second filler includes any one or more combinations of microcrystalline cellulose, pregelatinized starch, lactose, and mannitol. The lubricant includes one or more combinations of magnesium stearate, calcium stearate, and sodium stearate fumarate. The glidant includes one or more combinations of colloidal silicon dioxide and silicon dioxide.

[0031] In some embodiments, the disintegrant is prepared by mixing low-substituted hydroxypropyl cellulose (with a hydroxypropoxy content of 10 wt% to 12.9 wt%) and cross-linked sodium carboxymethyl cellulose in a mass ratio of 1:(0.8 to 1.2) (preferably 1:1), which can not only achieve the desired tablet disintegration effect, but also solve the problems of tablet compression delamination and cracking, and improve product stability.

[0032] After determining the dosage of binder, sustained-release matrix, and disintegrant through dissolution curve, it was found that different disintegrants have different effects on the product. The experiment found that when other disintegrants are used, flakes or stratification will occur during large-scale tablet compression. For example, when cross-linked polyvinylpyrrolidone is used alone as a disintegrant, the dissolution curve is qualified, but during large-scale production, particle stratification and flakes will occur, and the tablet stability is poor.

[0033] The present invention requires the use of low-substituted hydroxypropyl cellulose (hydroxypropoxy content of 10wt%~12.9wt%) and cross-linked sodium carboxymethyl cellulose in combination to solve the above problems. When low-substituted hydroxypropyl cellulose is used alone as a disintegrant, no particle stratification, flakes, etc. occur during mass production, but the tablet stability is poor and the dissolution curve is slow. Cross-linked sodium carboxymethyl cellulose can enhance tablet stability, but when cross-linked sodium carboxymethyl cellulose is used alone as a disintegrant, the dissolution is fast and the tablet stability is good, but particle stratification, flakes, etc. occur during mass production. After many tests, the composition and optimal ratio range of the disintegrant were determined. Too high or too low a ratio will lead to particle stratification, flakes or poor tablet stability.

[0034] Coating layer In some embodiments, the coating layer comprises a film coating premix. Specifically, by weight, the coating layer comprises 4 to 10 parts of the film coating premix.

[0035] In some specific embodiments, the method for preparing the eplerenone dapagliflozin compound sustained-release tablets of the present invention comprises the following steps: S1. Mix hydroxypropyl methylcellulose E3 or E5 with hydroxypropyl methylcellulose K4M in proportion and prepare an adhesive solution (preferably at a concentration of 6%-8%), then add dapagliflozin raw materials and mix evenly.

[0036] Since the amount of dapagliflozin raw material is small, the present invention dissolves the dapagliflozin raw material in the binder solution and then sprays it into the granulation, wrapping it on the surface of eplerenone and other particles, so that the small-sized dapagliflozin can be distributed more evenly, solving the problem of uneven dapagliflozin content. The dapagliflozin raw material is sprayed into the granulation before tableting to achieve a sustained release effect and a more lasting drug effect.

[0037] S2. Dry-mix the first filler with the eplerenone raw material, and after the dry-mixing, add the solution obtained in S1 to granulate. The slurrying time is preferably 2-3 minutes, and the granulation is preferably continued for 1-3 minutes after the slurrying is completed.

[0038] S3. Add the solubilizer, pore-forming agent and sustained-release coating material into purified water in sequence to prepare a suspension solution.

[0039] S4. The material after granulation in S2 is granulated and dried (preferably with a drying loss of 2%-3%), and the suspension solution obtained in S3 is sprayed into the granulation and dried, preferably when the material has a drying loss of 1%-3%, the material is discharged.

[0040] S5. Add a glidant to the material in S4, granulate it, then add a disintegrant, a second filler and a lubricant, mix well and press into tablets to obtain sustained-release tablets.

[0041] S6. Film-coating the prepared sustained-release tablets to obtain film-coated tablets. Preferably, the film coating premix is ​​added to purified water to prepare a coating solution with a solid content of about 8%.

[0042] Example: The contents of the components in the examples and comparative examples are shown in Table 1.

[0043] Table 1

[0044] Example 1 (1) 4000 tablets were prepared, each tablet containing approximately 206 mg.

[0045] (2) Mix different types of HPMC in proportion, add hot water to swell it, then add cold water to prepare a 7% adhesive solution, then add dapagliflozin raw material and mix evenly.

[0046] (3) Pass lactose through a 40-mesh sieve, and then place the sieved lactose and the prescribed amount of eplerenone raw material into a wet granulator and mix for 10 minutes.

[0047] (4) After dry mixing is completed, the solution obtained in step 2 is added, and the slurry addition time is 2-3 minutes; after the slurry addition is completed, granulation is continued for 2 minutes.

[0048] (5) The wet material after granulation is wet granulated and crushed with a 4×4 mm square sieve at 600 rpm.

[0049] (6) Place sodium dodecyl sulfate, polyethylene glycol 1400, and ethyl cellulose in a beaker filled with purified water to prepare a 5% ethyl cellulose suspension solution and stir evenly.

[0050] (7) After wet granulation, the granules are placed in a fluidized bed granulator for drying. When the material has a drying weight loss of 2%-3%, the solution in step 6 is sprayed in. When the material has a drying weight loss of 1%-3%, the material is discharged.

[0051] (8) After drying, colloidal silicon dioxide is added to the material for dry granulation, and the granulation is performed using a φ1.0 mm round sieve at a rotation speed of 200 rpm.

[0052] (9) After drying, add low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate to the granules, mix well and press into tablets. The hardness of the tablets should be controlled at 40~80N.

[0053] (10) Add appropriate amount of purified water to the film coating premix to prepare a coating solution with a solid content of 8%, stir and set aside.

[0054] (11) Add the prepared sustained-release tablets into the coating pan and spray the prepared coating solution to obtain film-coated tablets. The coating weight gain is controlled at about 3%.

[0055] Example 2 (1) 4000 tablets were prepared, each tablet containing approximately 206 mg.

[0056] (2) Mix different types of HPMC in proportion, add hot water to swell it, then add cold water to prepare a 7% adhesive solution, then add dapagliflozin raw material and mix evenly.

[0057] (3) Pass lactose and microcrystalline cellulose through a 40-mesh sieve, and then put them into a wet granulator with the prescribed amount of eplerenone raw material and mix for 10 minutes.

[0058] (4) After dry mixing is completed, the solution obtained in step 2 is added, and the slurry addition time is 2-3 minutes; after the slurry addition is completed, granulation is continued for 2 minutes.

[0059] (5) The wet material after granulation is wet granulated and crushed with a 4×4 mm square sieve at 600 rpm.

[0060] (6) Place sodium dodecyl sulfate, polyethylene glycol 1500 and ethyl cellulose in a beaker filled with purified water in sequence to prepare a 5% ethyl cellulose suspension solution and stir evenly.

[0061] (7) After wet granulation, the granules are placed in a fluidized bed granulator for drying. When the material has a drying weight loss of 2%-3%, the solution in step 6 is sprayed in. When the material has a drying weight loss of 1%-3%, the material is discharged.

[0062] (8) After drying, colloidal silicon dioxide is added to the material for dry granulation, and the granulation is performed using a φ0.6 mm round sieve at a rotation speed of 200 rpm.

[0063] (9) After drying, add low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, pregelatinized starch, and magnesium stearate to the granules, mix well, and press into tablets. The hardness of the tablets should be controlled at 40~80N.

[0064] (10) Add appropriate amount of purified water to the film coating premix to prepare a coating solution with a solid content of 8%, stir and set aside.

[0065] (11) Add the prepared sustained-release tablets into the coating pan and spray the prepared coating solution to obtain film-coated tablets. The coating weight gain is controlled at about 3%.

[0066] Example 3 (1) 4000 tablets were prepared, each tablet containing approximately 206 mg.

[0067] (2) Mix different types of HPMC in proportion, add hot water to swell it, then add cold water to prepare a 7% adhesive solution, then add dapagliflozin raw material and mix evenly.

[0068] (3) Pass microcrystalline cellulose and mannitol through a 40-mesh sieve, and then put them into a wet granulator with the prescribed amount of eplerenone raw material and mix for 10 minutes.

[0069] (4) After dry mixing is completed, the solution obtained in step 2 is added, and the slurry addition time is 2-3 minutes; after the slurry addition is completed, granulation is continued for 2 minutes.

[0070] (5) The wet material after granulation is wet granulated and crushed with a 4×4 mm square sieve at 600 rpm.

[0071] (6) Place sodium dodecyl sulfate, polyethylene glycol 600 and cellulose acetate titanate in a beaker filled with purified water in sequence to prepare a 5% cellulose acetate titanate suspension solution and stir evenly.

[0072] (7) After wet granulation, the granules are placed in a fluidized bed granulator for drying. When the material has a drying weight loss of 2%-3%, the solution in step 6 is sprayed in. When the material has a drying weight loss of 1%-3%, the material is discharged.

[0073] (8) After drying, silicon dioxide is added to the material for dry granulation, and the granulation is performed using a φ1.5 mm circular sieve at a rotation speed of 400 rpm.

[0074] (9) After drying, add low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, mannitol, and calcium stearate to the granules, mix well, and press into tablets. The hardness of the tablets should be controlled at 40~80N.

[0075] (10) Add appropriate amount of purified water to the film coating premix to prepare a coating solution with a solid content of 8%, stir and set aside.

[0076] (11) Add the prepared sustained-release tablets into the coating pan and spray the prepared coating solution to obtain film-coated tablets. The coating weight gain is controlled at about 3%.

[0077] Example 4 (1) Prepare 4000 tablets, each tablet contains approximately 210 mg.

[0078] (2) Mix different types of HPMC in proportion, add hot water to swell it, then add cold water to prepare a 7% adhesive solution, then add dapagliflozin raw material and mix evenly.

[0079] (3) Pass lactose, corn starch and mannitol through a 40-mesh sieve, and then put them into a wet granulator with the prescribed amount of eplerenone raw material and mix for 10 minutes.

[0080] (4) After dry mixing is completed, the solution obtained in step 2 is added, and the slurry addition time is 2-3 minutes; after the slurry addition is completed, granulation is continued for 2 minutes.

[0081] (5) The wet material after granulation is wet granulated and crushed with a 4×4 mm square sieve at 600 rpm.

[0082] (6) Add Tween 80, polyethylene glycol 600 and hydroxypropyl cellulose acrylate copolymer into a beaker filled with purified water in sequence to prepare a 5% hydroxypropyl cellulose acrylate copolymer suspension solution and stir evenly.

[0083] (7) After wet granulation, the granules are placed in a fluidized bed granulator for drying. When the material has a drying weight loss of 2%-3%, the solution in step 6 is sprayed in. When the material has a drying weight loss of 1%-3%, the material is discharged.

[0084] (8) After drying, colloidal silicon dioxide is added to the material for dry granulation, and the granulation is performed using a φ1.0 mm round sieve at a rotation speed of 200 rpm.

[0085] (9) After drying, add low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and sodium stearate fumarate to the granules, mix well, and press into tablets. The hardness of the tablets should be controlled at 40~80N.

[0086] (10) Add appropriate amount of purified water to the film coating premix to prepare a coating solution with a solid content of 8%, stir and set aside.

[0087] (11) Add the prepared sustained-release tablets into the coating pan and spray the prepared coating solution to obtain film-coated tablets. The coating weight gain is controlled at about 5%.

[0088] Example 5 (1) 4000 tablets were prepared, each tablet containing approximately 204 mg.

[0089] (2) Mix different types of HPMC in proportion, add hot water to swell it, then add cold water to prepare a 7% adhesive solution, then add dapagliflozin raw material and mix evenly.

[0090] (3) Pass lactose and mannitol through a 40-mesh sieve, and then put them into a wet granulator with the prescribed amount of eplerenone raw material and mix for 10 minutes.

[0091] (4) After dry mixing is completed, the solution obtained in step 2 is added, and the slurry addition time is 2-3 minutes; after the slurry addition is completed, granulation is continued for 2 minutes.

[0092] (5) The wet material after granulation is wet granulated and crushed with a 4×4 mm square sieve at 600 rpm.

[0093] (6) Place sodium dodecyl sulfate, polyethylene glycol 600, polyethylene glycol 1400, and ethyl cellulose in a beaker filled with purified water in sequence to prepare a 5% ethyl cellulose suspension solution and stir evenly.

[0094] (7) After wet granulation, the granules are placed in a fluidized bed granulator for drying. When the material has a drying weight loss of 2%-3%, the solution in step 6 is sprayed in. When the material has a drying weight loss of 1%-3%, the material is discharged.

[0095] (8) After drying, colloidal silicon dioxide is added to the material for dry granulation, and the granulation is performed using a φ1.0 mm round sieve at a rotation speed of 200 rpm.

[0096] (9) After drying, add low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, lactose, and calcium stearate to the granules, mix well, and press into tablets. The hardness of the tablets should be controlled at 40~80N.

[0097] (10) Add appropriate amount of purified water to the film coating premix to prepare a coating solution with a solid content of 8%, stir and set aside.

[0098] (11) Add the prepared sustained-release tablets into the coating pan and spray the prepared coating solution to obtain film-coated tablets. The coating weight gain is controlled at about 2%.

[0099] Comparative Example 1 (1) 4000 tablets were prepared, each tablet containing approximately 206 mg.

[0100] (2) First add hot water to swell Hydroxypropyl methylcellulose E3 and then add cold water to prepare a 7% adhesive solution. Then add dapagliflozin raw material and mix well.

[0101] (3) Pass lactose through a 40-mesh sieve, and then place the sieved lactose and the prescribed amount of eplerenone raw material into a wet granulator and mix for 10 minutes.

[0102] (4) After dry mixing is completed, the solution obtained in step 2 is added, and the slurry addition time is 2-3 minutes; after the slurry addition is completed, granulation is continued for 2 minutes.

[0103] (5) The wet material after granulation is wet granulated and crushed with a 4×4 mm square sieve at 600 rpm.

[0104] (6) Place sodium dodecyl sulfate, polyethylene glycol 1400, and ethyl cellulose in a beaker filled with purified water to prepare a 5% ethyl cellulose suspension solution and stir evenly.

[0105] (7) After wet granulation, the granules are placed in a fluidized bed granulator for drying. When the material has a drying weight loss of 2%-3%, the solution in step 6 is sprayed in. When the material has a drying weight loss of 1%-3%, the material is discharged.

[0106] (8) After drying, colloidal silicon dioxide is added to the material for dry granulation, and the granulation is performed using a φ1.0 mm round sieve at a rotation speed of 200 rpm.

[0107] (9) After drying, add low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate to the granules, mix well and press into tablets. The hardness of the tablets should be controlled at 40~80N.

[0108] (10) Add appropriate amount of purified water to the film coating premix to prepare a coating solution with a solid content of 8%, stir and set aside.

[0109] (11) Add the prepared sustained-release tablets into the coating pan and spray the prepared coating solution to obtain film-coated tablets. The coating weight gain is controlled at about 3%.

[0110] Comparative Example 2 (1) 4000 tablets were prepared, each tablet containing approximately 206 mg.

[0111] (2) Add hot water to swell Hydroxypropyl methylcellulose K4M and then add cold water to prepare a 7% adhesive solution. Then add dapagliflozin raw materials and mix well.

[0112] (3) Pass lactose through a 40-mesh sieve, and then place the sieved lactose and the prescribed amount of eplerenone raw material into a wet granulator and mix for 10 minutes.

[0113] (4) After dry mixing is completed, the solution obtained in step 2 is added, and the slurry addition time is 2-3 minutes; after the slurry addition is completed, granulation is continued for 2 minutes.

[0114] (5) The wet material after granulation is wet granulated and crushed with a 4×4 mm square sieve at 600 rpm.

[0115] (6) Place sodium dodecyl sulfate, polyethylene glycol 1400, and ethyl cellulose in a beaker filled with purified water to prepare a 5% ethyl cellulose suspension solution and stir evenly.

[0116] (7) After wet granulation, the granules are placed in a fluidized bed granulator for drying. When the material has a drying weight loss of 2%-3%, the solution in step 6 is sprayed in. When the material has a drying weight loss of 1%-3%, the material is discharged.

[0117] (8) After drying, colloidal silicon dioxide is added to the material for dry granulation, and the granulation is performed using a φ1.0 mm round sieve at a rotation speed of 200 rpm.

[0118] (9) After drying, add low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate to the granules, mix well and press into tablets. The hardness of the tablets should be controlled at 40~80N.

[0119] (10) Add appropriate amount of purified water to the film coating premix to prepare a coating solution with a solid content of 8%, stir and set aside.

[0120] (11) Add the prepared sustained-release tablets into the coating pan and spray the prepared coating solution to obtain film-coated tablets. The coating weight gain is controlled at about 3%.

[0121] Comparative Example 3 (1) 4000 tablets were prepared, each tablet containing approximately 206 mg.

[0122] (2) Mix different types of HPMC in proportion, add hot water to swell it, then add cold water to prepare a 7% adhesive solution, then add dapagliflozin raw material and mix evenly.

[0123] (3) Pass lactose through a 40-mesh sieve, and then place the sieved lactose and the prescribed amount of eplerenone raw material into a wet granulator and mix for 10 minutes.

[0124] (4) After dry mixing is completed, the solution obtained in step 2 is added, and the slurry addition time is 2-3 minutes; after the slurry addition is completed, granulation is continued for 2 minutes.

[0125] (5) The wet material after granulation is wet granulated and crushed with a 4×4 mm square sieve at 600 rpm.

[0126] (6) Place sodium dodecyl sulfate, polyethylene glycol 1400, and ethyl cellulose in a beaker filled with purified water to prepare a 5% ethyl cellulose suspension solution and stir evenly.

[0127] (7) After wet granulation, the granules are placed in a fluidized bed granulator for drying. When the material has a drying weight loss of 2%-3%, the solution in step 6 is sprayed in. When the material has a drying weight loss of 1%-3%, the material is discharged.

[0128] (8) After drying, colloidal silicon dioxide is added to the material for dry granulation, and the granulation is performed using a φ1.0 mm round sieve at a rotation speed of 200 rpm.

[0129] (9) After drying, add cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate to the granules, mix well and press into tablets. The hardness of the tablets should be controlled at 40~80N.

[0130] (10) Add appropriate amount of purified water to the film coating premix to prepare a coating solution with a solid content of 8%, stir and set aside.

[0131] (11) Add the prepared sustained-release tablets into the coating pan and spray the prepared coating solution to obtain film-coated tablets. The coating weight gain is controlled at about 3%.

[0132] Comparative Example 4 (1) 4000 tablets were prepared, each tablet containing approximately 206 mg.

[0133] (2) Mix different types of HPMC in proportion, add hot water to swell it, then add cold water to prepare a 7% adhesive solution, then add dapagliflozin raw material and mix evenly.

[0134] (3) Pass lactose through a 40-mesh sieve, and then place the sieved lactose and the prescribed amount of eplerenone raw material into a wet granulator and mix for 10 minutes.

[0135] (4) After dry mixing is completed, the solution obtained in step 2 is added, and the slurry addition time is 2-3 minutes; after the slurry addition is completed, granulation is continued for 2 minutes.

[0136] (5) The wet material after granulation is wet granulated and crushed with a 4×4 mm square sieve at 600 rpm.

[0137] (6) Place sodium dodecyl sulfate, polyethylene glycol 1400, and ethyl cellulose in a beaker filled with purified water to prepare a 5% ethyl cellulose suspension solution and stir evenly.

[0138] (7) After wet granulation, the granules are placed in a fluidized bed granulator for drying. When the material has a drying weight loss of 2%-3%, the solution in step 6 is sprayed in. When the material has a drying weight loss of 1%-3%, the material is discharged.

[0139] (8) After drying, colloidal silicon dioxide is added to the material for dry granulation, and the granulation is performed using a φ1.0 mm round sieve at a rotation speed of 200 rpm.

[0140] (9) After drying, add low-substituted hydroxypropyl cellulose, microcrystalline cellulose and magnesium stearate to the granules, mix well and press into tablets. The hardness of the tablets should be controlled at 40~80N.

[0141] (10) Add appropriate amount of purified water to the film coating premix to prepare a coating solution with a solid content of 8%, stir and set aside.

[0142] (11) Add the prepared sustained-release tablets into the coating pan and spray the prepared coating solution to obtain film-coated tablets. The coating weight gain is controlled at about 3%.

[0143] Comparative Example 5 (1) 4000 tablets were prepared, each tablet containing approximately 206 mg.

[0144] (2) Mix different types of HPMC in proportion, add hot water to swell it, then add cold water to prepare a 7% adhesive solution, then add dapagliflozin raw material and mix evenly.

[0145] (3) Pass lactose through a 40-mesh sieve, and then place the sieved lactose and the prescribed amount of eplerenone raw material into a wet granulator and mix for 10 minutes.

[0146] (4) After dry mixing is completed, the solution obtained in step 2 is added, and the slurry addition time is 2-3 minutes; after the slurry addition is completed, granulation is continued for 2 minutes.

[0147] (5) The wet material after granulation is wet granulated and crushed with a 4×4 mm square sieve at 600 rpm.

[0148] (6) Place sodium dodecyl sulfate, polyethylene glycol 1400, and ethyl cellulose in a beaker filled with purified water to prepare a 5% ethyl cellulose suspension solution and stir evenly.

[0149] (7) After wet granulation, the granules are placed in a fluidized bed granulator for drying. When the material has a drying weight loss of 2%-3%, the solution in step 6 is sprayed in. When the material has a drying weight loss of 1%-3%, the material is discharged.

[0150] (8) After drying, colloidal silicon dioxide is added to the material for dry granulation, and the granulation is performed using a φ1.0 mm round sieve at a rotation speed of 200 rpm.

[0151] (9) After drying, add low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate to the granules, mix well and press into tablets. The hardness of the tablets should be controlled at 40~80N.

[0152] (10) Add appropriate amount of purified water to the film coating premix to prepare a coating solution with a solid content of 8%, stir and set aside.

[0153] (11) Add the prepared sustained-release tablets into the coating pan and spray the prepared coating solution to obtain film-coated tablets. The coating weight gain is controlled at about 3%.

[0154] Effect experiment 1 Dapagliflozin dissolution test The dissolution test was carried out according to the paddle method in the dissolution test method of Part IV Guiding Principle 0931 of the 2020 edition of the Chinese Pharmacopoeia. The dissolution of dapagliflozin in the prepared preparation was tested at 1h / 2h / 4h / 6h / 8h / 12h / 18h / 24h, respectively. The test results are as follows.

[0155] The dissolution curve in hydrochloric acid medium at pH = 1.2 is as follows Figure 1 and Table 2: Table 2

[0156] The dissolution curve in acetate medium at pH = 4.5 is as follows Figure 2 and Table 3: Table 3

[0157] The dissolution curve in pH = 6.8 phosphate medium is as follows Figure 3 and Table 4: Table 4

[0158] Effect experiment 2 Eplerenone dissolution test The dissolution test was carried out according to the paddle method in the dissolution test method of Part IV Guiding Principle 0931 of the 2020 edition of the Chinese Pharmacopoeia. The dissolution of eplerenone in the prepared preparation was measured at 1h / 2h / 4h / 6h / 8h / 12h / 18h / 24h, respectively. The test results are as follows.

[0159] The dissolution curve in hydrochloric acid medium at pH = 1.2 is as follows Figure 4 and Table 5: Table 5

[0160] The dissolution curve in acetate medium at pH = 4.5 is as follows Figure 5 and Table 6: Table 6

[0161] The dissolution curve in pH = 6.8 phosphate medium is as follows Figure 6 and Table 7: Table 7

[0162] Effect experiment 3: stability test The stability test was carried out in accordance with the method in the fourth guideline 9001 Stability Testing Guidelines for Active Pharmaceutical Ingredients and Preparations of the 2020 edition of the Chinese Pharmacopoeia. The appearance and impurities of the prepared preparations were tested. The test results are shown in Table 8 below.

[0163] Table 8 Accelerated test results

[0164] As can be seen from the above table and the accompanying drawings, the release of the sustained-release tablets of Examples 1 to 5 varies slightly according to the changes in the prescription composition and excipients, but all can be completely released by 24 hours. However, in Comparative Examples 1-5, the release has changed significantly due to changes in the binder, sustained-release skeleton material or disintegrant. Comparative Example 1 (E3 is used as the binder alone) has been completely released at 18 hours, which is too fast; Comparative Example 3 (cross-linked sodium carboxymethyl cellulose is used as the disintegrant) can be seen to release too fast, and the content at the end of the release is too high; Comparative Example 2 (K4M is used as the binder alone) and Comparative Example 5 (the ethyl cellulose content of the sustained-release skeleton is increased) are not completely released at 24 hours; Comparative Example 4 (low-substituted hydroxypropyl cellulose is used as the disintegrant alone) releases too slowly.

[0165] From the results of the accelerated test, it can be seen that the appearance, content, and impurity content of the eplerenone dapagliflozin compound sustained-release tablets of Examples 1 to 5 did not change significantly after six months of accelerated testing, and no particle stratification, flakes, etc. occurred. However, due to the different disintegrant compositions of Comparative Examples 1-5, particle stratification during tableting may lead to higher or lower content (particle stratification, flakes, etc. occurred in Comparative Example 3), and the accelerated test stability of Comparative Example 4 without cross-linked sodium carboxymethyl cellulose was poor.

[0166] The above is only a preferred embodiment of the present invention and does not limit the present invention in any form. Therefore, any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the content of the technical solution of the present invention shall fall within the scope of protection of the technical solution of the present invention.

Claims

1. An eplerenone-dapagliflozin compound sustained-release tablet, characterized in that: From the inside to the outside, it includes a pill core, a sustained-release coating layer, a tabletting auxiliary material layer and a coating layer; The pill core includes a first filler, dapagliflozin propylene glycol monohydrate, eplerenone and a binder; the binder is a combination of hypromellose E3 or hypromellose E5 and hypromellose K4M; The sustained-release coating layer comprises a sustained-release coating material, a pore-forming agent and a solubilizing agent; The tableting auxiliary material layer comprises a second filler, a glidant, a disintegrant and a lubricant; the disintegrant consists of low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose.

2. The eplerenone-dapagliflozin compound sustained-release tablet according to claim 1, characterized in that: In terms of weight, the pill core includes 80 to 120 parts of a first filler, 5.5 to 13.5 parts of dapagliflozin propylene glycol monohydrate, 20 to 55 parts of eplerenone, and 9 to 12 parts of a binder.

3. The eplerenone-dapagliflozin compound sustained-release tablet according to claim 1 or 2, characterized in that: The binder is composed of hypromellose E3 or hypromellose E5 and hypromellose K4M in a mass ratio of 1:(1.8-2.2).

4. The eplerenone-dapagliflozin compound sustained-release tablet according to claim 1, characterized in that: In parts by weight, the sustained-release coating layer comprises 5 to 10 parts of sustained-release coating material, 1 to 2 parts of pore-forming agent, and 4 to 6 parts of solubilizer.

5. The eplerenone-dapagliflozin compound sustained-release tablet according to claim 1 or 4, characterized in that: The sustained-release coating material is one or more combinations of ethyl cellulose aqueous dispersion, cellulose acetate phthalate, or hydroxypropyl cellulose acrylate copolymer.

6. The eplerenone-dapagliflozin compound sustained-release tablet according to claim 1, characterized in that: In terms of weight, the tableting auxiliary material layer includes 10 to 20 parts of a second filler, 7 to 15 parts of a disintegrant, 0.5 to 1 part of a lubricant, and 0.5 to 1 part of a glidant.

7. The eplerenone-dapagliflozin compound sustained-release tablet according to claim 1 or 6, characterized in that: The disintegrant is composed of low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose in a mass ratio of 1:(0.8-1.2).

8. The eplerenone-dapagliflozin compound sustained-release tablet according to claim 1, characterized in that: The coating layer includes a film coating premix.

9. A method for preparing the eplerenone-dapagliflozin compound sustained-release tablets according to any one of claims 1 to 8, characterized in that: The following steps are involved: S1. Mixing hydroxypropyl methylcellulose E3 or E5 with hydroxypropyl methylcellulose K4M to prepare an adhesive solution, and then adding dapagliflozin raw materials and mixing evenly; S2. The first filler and the eplerenone raw material are dry mixed, and then the solution obtained in S1 is added for granulation; S3. The solubilizer, pore-forming agent, and sustained-release coating material are added to water to prepare a suspension solution; S4. After the granulated material in S2 is dried, the suspension solution obtained in S3 is sprayed into the granulation and dried; S5. Add a glidant to the material obtained in S4, then add a disintegrant, a second filler and a lubricant, mix well and tablet to obtain a sustained-release tablet; S6. Film-coating the sustained-release tablets prepared in S5 to obtain the eplerenone-dapagliflozin compound sustained-release tablets.

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