Double-layer tablet containing DPP-4 inhibitor, SGLT-2 inhibitor and metformin

Abstract

The present disclosure relates to a bilayer tablet comprising a DPP-4 inhibitor, an SGLT-2 inhibitor, and metformin. In particular, the present disclosure provides a bilayer tablet containing repagliptin, gigliflozin, and metformin.

Description

Technical Field

[0001] The present disclosure belongs to the field of pharmaceutical preparations, and specifically relates to a compound double-layer tablet comprising a DPP-4 inhibitor, an SGLT-2 inhibitor and metformin, in particular a double-layer tablet comprising repagliptin, henggliflozin and metformin. Background Art

[0002] Type ii diabetes is the most common form of diabetes, accounting for 90% of the diabetic cases. The patient suffering from type ii diabetes cannot properly respond to insulin, and insulin, as a hormone, usually allows the body to convert blood sugar into energy or store blood sugar in cells for later use. The problem about type ii diabetes is that it is called the state of insulin resistance, in which the body produces normal amounts or even higher amounts of insulin, but some mechanisms prevent insulin from transferring glucose into cells. Because the body cannot properly use insulin, the glucose in the blood rises to an unsafe level, which is referred to as the state of hyperglycemia. Over time, continued hyperglycemia causes glucose toxicity, which makes insulin resistance more serious and facilitates pancreatic beta cell dysfunction. The degree of continued hyperglycemia is directly related to diabetic microvascular complications and can also facilitate macrovascular complications. Therefore, hyperglycemia constantly circulates harmful effects, which has increased the weight of control and complications of type ii diabetes.

[0003] Metformin is a first-line treatment recommended by multiple diabetes treatment guidelines. It improves glucose tolerance and lowers basal and postprandial blood glucose in patients with type 2 diabetes. Metformin works by increasing peripheral glucose uptake and utilization, reducing hepatic glucose production, decreasing intestinal glucose absorption, and improving insulin sensitivity. Except in specific circumstances, metformin does not cause hypoglycemia or hyperinsulinemia in patients with type 2 diabetes or healthy subjects. While insulin secretion remains unchanged with metformin treatment, fasting insulin levels and the daily plasma insulin response may be reduced.

[0004] Retagliptin is a member of the dipeptidyl peptidase-4 (DPP-4) inhibitor family. Its compound name is (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester. Retagliptin inhibits DPP-4 hydrolysis of incretin hormones, thereby increasing plasma concentrations of the active forms of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This increases insulin release in a glucose-dependent manner and reduces glucagon levels, ultimately lowering blood sugar.

[0005] Henggliflozin is a sodium-glucose cotransporter 2 (SGLT-2) inhibitor. Its compound is 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-β-L-idopyranose. Henggliflozin selectively inhibits SGLT2 in the kidneys, reducing the reabsorption of glucose filtered through the renal tubules and lowering the renal threshold for glucose, thereby increasing urinary glucose excretion. This improves insulin sensitivity and delays the onset of diabetic complications, thereby normalizing plasma glucose levels.

[0006] Studies have shown that for many patients with type 2 diabetes, if the above-mentioned oral hypoglycemic drugs are used alone as anti-diabetic treatment, blood sugar cannot be adequately controlled during long-term treatment. Therefore, a combination therapy of two or more oral hypoglycemic drugs is usually adopted to exert a synergistic hypoglycemic effect, thereby better controlling the blood sugar of patients with type 2 diabetes. At present, the combined use of DPP-4 inhibitor series drugs and SGLT-2 inhibitor series drugs has recently been recognized by the academic community as having excellent efficacy and effect in the treatment of diabetes, and ternary preparations with metformin are being studied. However, the combined prescription of two or more oral hypoglycemic drugs may lead to complicated treatment plans, which are difficult for many patients to follow. Therefore, the current better medication regimen is to combine two or more oral hypoglycemic drugs into a single tablet without increasing the complexity of the patient's daily treatment plan. Among them, dual-release tablets containing a rapid-release portion and a sustained-release portion are currently the hotspot of research.

[0007] However, existing triple-combination hypoglycemic oral dual-release preparations often use a coating process, which is complex and unsuitable for large-scale production. Bi-layer tablets, another process for producing triple-combination hypoglycemic oral dual-release preparations, present issues such as the risk of tablet splitting, leaving significant room for improvement. Summary of the Invention

[0008] The present disclosure provides a compound double-layer tablet comprising:

[0009] (1) a sustained-release layer comprising metformin or a pharmaceutically acceptable salt thereof, and further comprising one or more of a filler, a binder, a sustained-release matrix, a lubricant, and a glidant;

[0010] (2) an immediate-release layer, which comprises repagliptin or a pharmaceutically acceptable salt thereof, and henggliflozin or a pharmaceutically acceptable salt thereof, or a complex thereof, and further comprises one or more of a filler, a disintegrant, a lubricant, and a glidant;

[0011] (3) a coating layer, wherein the coating solvent is a mixture of ethanol and water, and the content of ethanol is 80-95% w / w.

[0012] In some embodiments, the content of ethanol in the coating solvent is specifically 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% or a value between any two of these numbers.

[0013] In some embodiments, the content of ethanol in the coating solvent is 85 - 90% w / w.

[0014] In some embodiments, the content of ethanol in the coating solvent is 90% w / w.

[0015] In some embodiments, the metformin or its pharmaceutically acceptable salt can be metformin hydrochloride. In some embodiments, the repaglinide or its pharmaceutically acceptable salt can be repaglinide phosphate. In some embodiments, the empagliflozin or its pharmaceutically acceptable salt or its complex can be empagliflozin proline.

[0016] In some embodiments, the filler is selected from one or more of microcrystalline cellulose, mannitol, pregelatinized starch, dextrin, sucrose, lactose. In some embodiments, the filler is microcrystalline cellulose.

[0017] In some embodiments, based on the total weight of the sustained-release layer and the immediate-release layer, the filler content in the sustained-release layer is 0 - 10%, specifically 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or a value between any two of these numbers.

[0018] In some embodiments, based on the total weight of the sustained-release layer and the immediate-release layer, the filler content in the immediate-release layer is 5 - 30%, specifically 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30% or a value between any two of these numbers.

[0019] In some embodiments, the binder is selected from one or more of povidone, starch paste, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose. In some embodiments, the binder is povidone. In some embodiments, the binder is sodium carboxymethylcellulose.

[0020] In some embodiments, based on the total weight of the sustained-release layer and the immediate-release layer, the filler content in the immediate-release layer is 0.5-10%, specifically 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or a value between any two of them.

[0021] The sustained-release matrix can be any sustained-release matrix material known in the art. In some embodiments, the sustained-release matrix is selected from one or more of hypromellose, methylcellulose, ethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and povidone. In some embodiments, the sustained-release matrix is hypromellose.

[0022] In some embodiments, based on the total weight of the sustained-release layer and the immediate-release layer, the sustained-release matrix content in the sustained-release layer is 5-30%, specifically 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30% or a value between any two of them.

[0023] In some embodiments, the disintegrant is selected from one or several of sodium croscarmellose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and crospovidone. In some embodiments, the disintegrant is sodium croscarmellose.

[0024] In some embodiments, based on the total weight of the sustained-release layer and the immediate-release layer, the disintegrant content in the immediate-release layer is 0.05-5%, specifically 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or a value between any two of them.

[0025] In some embodiments, the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, talc, hydrogenated vegetable oil, and polyethylene glycol. In some embodiments, the lubricant is magnesium stearate. In some embodiments, based on the total weight of the sustained-release layer and the immediate-release layer, the lubricant content in both the sustained-release layer and the immediate-release layer is 0.05-5%.

[0026] In some embodiments, the glidant is selected from colloidal silica and talc powder. In some embodiments, the glidant is colloidal silica. In some embodiments, based on the total weight of the sustained-release layer and the immediate-release layer, the glidant content in both the sustained-release layer and the immediate-release layer is 0.05-5%.

[0027] In some embodiments, based on the total weight of the sustained-release layer and the immediate-release layer, the sustained-release layer comprises: 40-70% metformin hydrochloride, 0-10% microcrystalline cellulose, 0-10% polyvinylpyrrolidone, 0-10% sodium carboxymethylcellulose, 5-30% hypromellose, 0.05-2% magnesium stearate, and 0.05-2% colloidal silica.

[0028] In some embodiments, based on the total weight of the sustained-release layer and the immediate-release layer, the immediate-release layer comprises: 0.05-5% empagliflozin proline, 0.5-15% repaglinide phosphate, 5-30% microcrystalline cellulose, 0.05-5% cross-linked sodium carboxymethylcellulose, 0.05-2% magnesium stearate, and 0.05-2% colloidal silica.

[0029] The present disclosure provides a compound bilayer tablet, which comprises:

[0030] 1) A sustained-release layer, comprising, based on the total weight of the two layers: 40-70% metformin hydrochloride, 0-10% microcrystalline cellulose, 0-10% polyvinylpyrrolidone, 0-10% sodium carboxymethylcellulose, 5-30% hypromellose, 0.05-2% magnesium stearate, and 0.05-2% colloidal silica;

[0031] 2) An immediate-release layer, comprising, based on the total weight of the two layers: 0.05-5% empagliflozin proline, 0.5-15% repaglinide phosphate, 5-30% microcrystalline cellulose, 0.05-5% cross-linked sodium carboxymethylcellulose, 0.05-2% magnesium stearate, and 0.05-2% colloidal silica;

[0032] 3) A coating layer, wherein the solvent used for coating is selected from a mixed solution of ethanol and water, and the ethanol content is selected from 80-95% w / w, preferably 85-90% w / w.

[0033] The compound bilayer tablet may contain 5 mg to 10 mg of empagliflozin free base, 50 mg to 100 mg of repaglinide free base, and 500 mg to 1000 mg of metformin hydrochloride per unit dosage form. For example, the compound bilayer tablet may contain 5 mg of empagliflozin, 50 mg of repaglinide, and 750 mg of metformin hydrochloride per unit dosage form, or may contain 10 mg of empagliflozin, 100 mg of repaglinide, and 1000 mg of metformin hydrochloride.

[0034] The present disclosure also provides a method for preparing a compound bilayer tablet, comprising: pressing a sustained-release layer containing metformin and a quick-release layer containing repaglinide and hengliflozin into a bilayer tablet, and then coating the tablet with an ethanol solution as a coating solvent, wherein the content of the ethanol solution is selected from 80-95% w / w.

[0035] In some embodiments, the content of the ethanol solution is selected from 85-90% w / w.

[0036] In some embodiments, the method for preparing a compound bilayer tablet comprises:

[0037] 1) preparing sustained-release layer granules containing metformin hydrochloride by wet granulation;

[0038] 2) preparing immediate-release layer granules containing proline-containing henggliflozin and retagliptin phosphate using a dry granulation method;

[0039] 3) Pre-compressing the sustained-release layer granules obtained in step 1 and the immediate-release layer granules obtained in step 2 into plain tablets;

[0040] 4) coating the plain tablets obtained in step 3.

[0041] Another aspect of the present disclosure provides use of the aforementioned compound double-layer tablet in preparing a medicament for treating type II diabetes.

[0042] The present disclosure also provides a method for treating type II diabetes, comprising administering an effective amount of the aforementioned bilayer tablet to a patient.

[0043] The numerical values in this disclosure are instrumental measurements or calculated values after instrumental measurement, and are subject to a certain degree of error. Generally speaking, a value within a reasonable error range of plus or minus 10% is within the reasonable error range. Of course, the context in which the numerical value is used must be considered. For example, the total impurity content, which is a value with an error variation of no more than plus or minus 10% after measurement, can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.

[0044] The applicant unexpectedly discovered that when a high-concentration ethanol solution is used as a coating solvent for the compound double-layer tablets, the surface of the prepared double-layer tablets is smooth and free of cracks, and they will not crack even when placed under high humidity conditions. The impurity content can also be effectively controlled, significantly improving the quality attributes of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 Comparison of the appearance of purified water-coated tablets after being placed at 25°C / 75% for 48 hours

[0046] Figure 2Appearance comparison of 50% ethanol-coated tablets after being placed at 25°C / 75% for 48 hours

[0047] Figure 3 Appearance comparison of 80% ethanol-coated tablets after being placed at 25°C / 75% for 48 hours

[0048] Figure 4 Appearance comparison of 85% ethanol-coated tablets after being placed at 25°C / 75% for 48 hours

[0049] Figure 5 Appearance comparison of 90% ethanol-coated tablets after being placed at 25°C / 75% for 48 hours Specific implementation manners

[0050] The following further illustrates the present disclosure with reference to specific embodiments. Those skilled in the art can understand that these embodiments are only used to illustrate the present disclosure and do not limit the scope of the present disclosure in any way.

[0051] Example 1, 5mg / 50mg / 750mg specification

[0052] Table 1

[0053]

[0054]

[0055] Preparation method:

[0056] 1) Preparation of sustained-release layer granules

[0057] Prepare the binder according to the prescription ratio in the sustained-release layer in Table 1, weigh the internal addition materials, prepare the granules by wet granulation, screen the granules after drying, and mix the dry granules with the external addition excipients and reserve for use.

[0058] 2) Preparation of immediate-release layer granules

[0059] Weigh the internal addition materials according to the prescription composition of the immediate-release layer in Table 1, prepare the granules by dry granulation, and mix the granules with the external addition excipients and reserve for use.

[0060] 3) Tabletting

[0061] Place the sustained-release layer granules in the die of the tabletting machine, pre-press, and then place the immediate-release layer granules in the die of the tabletting machine to press into double-layer plain tablets.

[0062] 4) Coating

[0063] Weigh the prescribed amount of film coating premix to prepare the coating solution, and coat the plain tablets.

[0064] Example 2, 10mg / 100mg / 1000mg specification

[0065] Table 2

[0066]

[0067]

[0068] Preparation method:

[0069] 1) Preparation of sustained-release layer granules

[0070] According to the formulation of the sustained-release layer in Table 2, the internal materials were weighed and wet granulated using purified water as a wetting agent. After drying, the granules were granulated. The dry granules were mixed with the external excipients and then set aside.

[0071] 2) Preparation of immediate-release layer granules

[0072] According to the prescription composition of the immediate-release layer in Table 2, the internal materials were weighed, and granules were prepared by dry granulation. The granules were mixed with the external excipients and set aside.

[0073] 3) Tablet pressing

[0074] The sustained-release layer granules are placed in the die of the tablet press and pre-compressed, and then the immediate-release layer granules are placed in the die of the tablet press and compressed into double-layer plain tablets.

[0075] 4) Coating

[0076] Weigh the prescribed amount of film coating premix to prepare a coating solution, and coat the plain tablets.

[0077] Example 3 Screening of coating solvents

[0078] 1) Sample preparation

[0079] A gastric-soluble film coating premix was used as the coating material. A coating solution with an 8% solids content was prepared using 90% aqueous ethanol, 85% aqueous ethanol, 80% aqueous ethanol, 50% aqueous ethanol, and purified water as the coating solvents, in that order by weight. The two-layer plain tablets prepared in Example 1 were coated with these coating solutions using the different solvent systems.

[0080] 2) Tablet appearance inspection

[0081] The samples prepared with different coating solutions were placed in a sample box at 25°C / 75% humidity for 48 hours, and the changes in the appearance of the samples were observed. The specific results are shown in Table 3 and Figures 1-5 .

[0082] Table 3

[0083]

[0084] Conclusion: For the double-layer tablets prepared with purified water and 50% ethanol as the coating solvents, there were inconspicuous cracks on the surface of the coated tablets at the initial stage. After being placed at 25°C / 75% high humidity for 48 hours, the cracks significantly deepened, presenting a risk of lamination. When the ethanol concentration was increased to 80%, almost no cracks could be observed on the surface of the coated tablets at the initial stage. After being placed at 25°C / 75% high humidity for 48 hours, the cracks slightly deepened, and the lamination situation improved. Further increasing the ethanol concentration to 85% and above, whether at the initial stage or after being placed at high humidity for a period of time, the surface of the coated tablets remained smooth and flat, without the risk of lamination.

Claims

1. A compound double-layer tablet, comprising: (1) A sustained-release layer, which contains metformin or a pharmaceutically acceptable salt thereof, and also contains one or more of a filler, a binder, a sustained-release matrix, a lubricant, and a glidant; (2) An immediate-release layer, which contains repaglinide or a pharmaceutically acceptable salt thereof, and empagliflozin or a pharmaceutically acceptable salt or a complex thereof, and also contains one or more of a filler, a disintegrant, a lubricant, and a glidant; (3) A coating layer, wherein the solvent used for coating is selected from ethanol solutions, and the ethanol content is selected from 80-95% w / w, preferably 85-90% w / w.

2. The double-layer tablet according to claim 1, wherein the filler is selected from one or more of microcrystalline cellulose, mannitol, pregelatinized starch, dextrin, sucrose, and lactose, preferably microcrystalline cellulose, and more preferably the filler contents in the sustained-release layer and the immediate-release layer are 0-10% and 5-30% respectively based on the total weight of the two layers.

3. The double-layer tablet according to claim 1, wherein the binder is selected from one or more of povidone, starch paste, methylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose, and sodium carboxymethylcellulose, preferably povidone and / or sodium carboxymethylcellulose, and more preferably the binder content in the sustained-release layer is 0.5-10% based on the total weight of the two layers.

4. The double-layer tablet according to claim 1, wherein the sustained-release matrix is selected from one or more of hypromellose, methylcellulose, ethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and povidone, preferably hypromellose, and more preferably the sustained-release matrix content in the sustained-release layer is 5-30% based on the total weight of the two layers.

5. The double-layer tablet according to claim 1, wherein the disintegrant is selected from one or several of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and crospovidone, preferably croscarmellose sodium, and more preferably the disintegrant content in the immediate-release layer is 0.05-5% based on the total weight of the two layers.

6. The double-layer tablet according to claim 1, wherein the lubricant is selected from magnesium stearate, sodium stearyl fumarate, talc, hydrogenated vegetable oil, and polyethylene glycol 6000, preferably magnesium stearate, and more preferably the lubricant contents in the sustained-release layer and the immediate-release layer are both 0.05-5% based on the total weight of the two layers.

7. The double-layer tablet according to claim 1, wherein the glidant is selected from talc and colloidal silicon dioxide, preferably colloidal silicon dioxide, and more preferably the glidant contents in the sustained-release layer and the immediate-release layer are both 0.05-5% based on the total weight of the two layers.

8. The double-layer tablet according to any one of claims 1-7, wherein the sustained-release layer contains, based on the total weight of the two layers: 40-70% of metformin hydrochloride, 0-10% of microcrystalline cellulose, 0-10% of povidone, 0-10% of sodium carboxymethylcellulose, 5-30% of hypromellose, 0.05-2% of magnesium stearate, and 0.05-2% of colloidal silicon dioxide.

9. The bilayer tablet according to any one of claims 1-8, wherein the immediate-release layer comprises, based on the total weight of the two layers: 0.05-5% of empagliflozin proline, 0.5-15% of repaglinide phosphate, 5-30% of microcrystalline cellulose, 0.05-5% of croscarmellose sodium, 0.05-2% of magnesium stearate, and 0.05-2% of colloidal silicon dioxide.

10. The bilayer tablet according to any one of claims 1-9, comprising: 1) a sustained-release layer comprising, based on the total weight of the two layers: 40-70% of metformin hydrochloride, 0-10% of microcrystalline cellulose, 0-10% of povidone, 0-10% of sodium carboxymethylcellulose, 5-30% of hypromellose, 0.05-2% of magnesium stearate, and 0.05-2% of colloidal silicon dioxide; 2) an immediate-release layer comprising, based on the total weight of the two layers: 0.05-5% of empagliflozin proline, 0.5-15% of repaglinide phosphate, 5-30% of microcrystalline cellulose, 0.05-5% of croscarmellose sodium, 0.05-2% of magnesium stearate, and 0.05-2% of colloidal silicon dioxide; 3) a coating layer, wherein the solvent used for coating is selected from a mixed solution of ethanol and water, and the content of ethanol is selected from 80-95% w / w, preferably 85-90% w / w.

11. The bilayer tablet according to claims 1-10, wherein the coating material of the coating layer is a gastric-soluble film coating premix.

12. A method for preparing a compound bilayer tablet, comprising: The step of pressing a sustained-release layer containing metformin and an immediate-release layer containing repaglinide and empagliflozin into a bilayer tablet, and then coating it with an ethanol solution as a coating solvent, wherein the content of the ethanol solution is selected from 80-95% w / w, preferably 85-90% w / w.

13. Use of the bilayer tablet according to any one of claims 1-11 in the preparation of a medicament for the treatment of type II diabetes.

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