Saxagliptin metformin sustained-release tablets and preparation method thereof

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to saxagliptin metformin sustained-release tablets and a preparation method thereof. The saxagliptin metformin sustained-release tablets include saxagliptin pellets, metformin hydrochloride pellets and color coatings; the saxagliptin pellets include the following raw materials: saxagliptin monohydrate, silicon dioxide pellet core, hypromellose, talcum powder, hydrochloric acid; the metformin hydrochloride pellets include the following raw materials: metformin hydrochloride, ethyl cellulose, triethyl citrate; the color coating includes the following raw materials: gastric soluble film coating premix, hydrochloric acid, polyethylene glycol. The drug quality of the present invention is stable, the dosage is accurate, the production time is short, and the quality is consistent with the original preparation.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to saxagliptin metformin sustained-release tablets and a preparation method thereof. Background Art

[0002] Diabetes mellitus (DM) is a common chronic comprehensive disease that plagues the world. Diabetes is a common and frequently occurring disease characterized by high blood sugar. There are two types of diabetes: insulin-dependent (IDDM, type 1) and non-insulin-dependent (NIDDM, type 2). Type 2 diabetes accounts for about 90%-95% of the total number of diabetic patients, and has become the third most serious chronic disease that endangers human health after tumors and cardiovascular diseases. The current treatment methods are mainly to change lifestyle, lower blood sugar and enhance insulin sensitivity. Commonly used anti-diabetic drugs in clinical practice are mainly insulin-glycosidase inhibitors: biguanides, thiazolidinediones, sulfonylureas and non-sulfonylurea insulin sensitizers. With the deepening of research, many new targets for the etiology of type 2 diabetes have been continuously developed, and a series of new anti-diabetic drugs that can sustainably control blood sugar levels and effectively block the progression of the disease have emerged. Among them, the research on drugs targeting dipeptidyl peptidase-4 (DPP-4) is the most prominent.

[0003] Saxagliptin metformin extended-release tablets are a glucose-lowering drug that combines the complementary mechanisms of action of saxagliptin and metformin. They are suitable for adult patients with type 2 diabetes who are receiving combination therapy with saxagliptin and metformin to improve blood sugar control in such patients.

[0004] Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor and an incretin-type glucose-lowering drug. Unlike other drugs that simply promote insulin secretion, incretin-type glucose-lowering drugs "command" the production of insulin only when blood sugar rises, so they have a protective effect on pancreatic β-cell function. Studies have shown that incretin-type glucose-lowering drugs can not only promote the secretion of insulin by pancreatic β-cells and lower blood sugar, but also reduce β-cell apoptosis, thereby delaying the progression of the disease, and are expected to fundamentally curb the progression of type 2 diabetes.

[0005] Metformin is a biguanide hypoglycemic drug that improves blood sugar tolerance and lowers basal and postprandial blood sugar in patients with type 2 diabetes. Metformin can reduce the production of glycogen and the absorption of glucose in the small intestine, and can increase insulin sensitivity by increasing the uptake and utilization of glucose by peripheral tissues, thereby playing a hypoglycemic role. At present, metformin is a widely used hypoglycemic drug in developed countries around the world, especially for the treatment of patients with obesity, high plasma insulin, secondary sulfonylurea failure, and poor insulin treatment and control of type 1 diabetes.

[0006] Metformin and saxagliptin are complementary in the treatment mechanism of diabetes. When these two drugs are used in combination, the therapeutic effect of the drugs can be enhanced. Therefore, in the prior art, sustained-release metformin and immediate-release saxagliptin are made into compound preparations. A fixed dose of saxagliptin and metformin hydrochloride form a sustained-release compound preparation. The compound preparation has an enhanced therapeutic effect, reduces the amount of drugs to be taken, simplifies the treatment method, and can improve the patient's treatment compliance.

[0007] Compared with ordinary preparations, sustained-release preparations can extend the dosing interval by reducing the drug release rate, which can reduce the number of medications and improve patient compliance. Moreover, sustained-release preparations can enable the human body to maintain blood drug concentrations for a longer period of time, avoiding the "peak and valley" phenomenon caused by frequent dosing, thereby improving the safety, effectiveness and adaptability of the drug. Due to the short half-life of metformin, ordinary preparations need to be taken 2-3 times a day. Therefore, saxagliptin metformin sustained-release tablets are of great significance to the clinical treatment of diabetic patients.

[0008] Saxagliptin metformin extended-release tablets have been marketed in the United States, the European Union, Russia and other countries and regions, and were launched in China on May 18, 2017. The English trade name is kombiglyze XR and the Chinese trade name is Anlige. There are three specifications, namely, each tablet contains saxagliptin 5mg / metformin hydrochloride 500mg, each tablet contains saxagliptin 5mg / metformin hydrochloride 1000mg, and each tablet contains saxagliptin 2.5mg / metformin hydrochloride 1000mg.

[0009] Chinese invention patent CN102266325A discloses a method for preparing saxagliptin metformin sustained-release tablets by direct tableting of all powders. The method uses a low-solubility metformin hydrochloride crystal in combination with a common matrix material to achieve a sustained-release effect of metformin hydrochloride. The preparation process is sequentially: mixing saxagliptin (crushed and sieved) + excipients (crushed and sieved), mixing metformin hydrochloride + excipients, adding equal amounts of total mixing, and tableting. Due to the large difference in the amount of saxagliptin (specification 5mg-30mg) and metformin hydrochloride (specification 500mg-800mg) used in the preparation, it is very easy to cause uneven mixing. In addition, the dry mixing process is also prone to cause intramolecular cyclization of saxagliptin to form cyclic amidine.

[0010] Chinese invention patent CN112494485A discloses a saxagliptin and metformin hydrochloride sustained-release tablet and its preparation process. The sustained-release tablet is composed of a metformin hydrochloride sustained-release tablet core, a sealing layer, a saxagliptin upper drug layer, and a colored layer from the inside to the outside; wherein the metformin hydrochloride sustained-release tablet core includes metformin hydrochloride, cellulose acetate, a dissolving skeleton material, and an adhesive; the saxagliptin upper drug layer includes saxagliptin, adipic acid, and Opadry II coating materials. Although this process solves the problems of poor uniformity of saxagliptin content and intramolecular cyclization degradation to a certain extent, N-formyl adduct (NFA) impurities were found in the process of preparing the second coating layer. The reaction principle is that the primary amine of saxagliptin is formylated by the reaction of saxagliptin with formylated substances (such as formic acid, formate, formate, formic anhydride). In addition, due to the performance limitations of current domestic coating equipment, it was also found during the preparation of the second layer of coating that the controllability of the saxagliptin drug layer coating process still needs to be improved.

[0011] In summary, how to completely solve the problems of poor content uniformity and instability of saxagliptin caused by the disparity in the dosage of metformin hydrochloride and saxagliptin, and ensure that the saxagliptin layer process is stable and controllable is of utmost importance. Summary of the invention

[0012] In order to solve the above technical problems, the present invention proposes a saxagliptin metformin sustained-release tablet and a preparation method thereof. The saxagliptin metformin sustained-release tablet is an oral tablet containing metformin hydrochloride and saxagliptin, and has stable drug quality, accurate dosage, and quality consistent with the original preparation; the preparation method has simple process, good production continuity, high degree of mechanization, and is suitable for industrial production.

[0013] The present invention is achieved through the following technical solutions:

[0014] The saxagliptin metformin sustained-release tablets of the present invention are oral tablets containing metformin hydrochloride and saxagliptin monohydrate, including saxagliptin pellets, metformin hydrochloride pellets and color coatings;

[0015] The saxagliptin microcapsules include the following raw materials: saxagliptin monohydrate, silicon dioxide pellet core, hydroxypropyl methylcellulose, talc, and hydrochloric acid; the metformin hydrochloride microcapsules include the following raw materials: metformin hydrochloride, ethyl cellulose, and triethyl citrate; and the color coating includes the following raw materials: gastric soluble film coating premix, hydrochloric acid, and polyethylene glycol.

[0016] Preferably, the saxagliptin microcapsules include the following raw materials in parts by weight: 2.65-5.29 parts of saxagliptin monohydrate, 20-100 parts of silicon dioxide pellet cores, 1-3 parts of hypromellose, 0.1-0.5 parts of talc, and 10-40 parts of hydrochloric acid.

[0017] Preferably, the metformin hydrochloride microcapsules include the following raw materials in parts by weight: 500-1000 parts of metformin hydrochloride, 2-6 parts of ethyl cellulose, and 2-8 parts of triethyl citrate.

[0018] Preferably, the color coating comprises the following raw materials in parts by weight: 200-500 parts of gastric soluble film coating premix, 10-40 parts of hydrochloric acid, and 10-40 parts of polyethylene glycol.

[0019] Preferably, the saxagliptin metformin sustained-release tablets further include excipients, microcrystalline cellulose and magnesium stearate.

[0020] Preferably, in parts by weight, the amount of microcrystalline cellulose is 75-300 parts, and the amount of magnesium stearate is 5-15 parts.

[0021] The method for preparing the saxagliptin metformin sustained-release tablets of the present invention comprises the following steps:

[0022] (1) evenly dispersing saxagliptin monohydrate, hydroxypropyl methylcellulose and talc in water to obtain a saxagliptin coating solution, and acidifying the saxagliptin coating solution with hydrochloric acid to control the pH value to be 1-4;

[0023] (2) placing the silica pellet cores into a fluidized bed, spraying the acidified saxagliptin coating solution into the cores, and coating the cores to obtain saxagliptin pellets;

[0024] (3) Dissolve ethyl cellulose in ethanol, then add triethyl citrate and stir evenly, add to metformin hydrochloride to prepare a wet material, and use an extrusion spheronizer to prepare metformin hydrochloride microcapsules;

[0025] (4) Evenly mixing the metformin hydrochloride pellets, saxagliptin pellets, microcrystalline cellulose and magnesium stearate, and tableting to obtain saxagliptin metformin sustained-release tablets;

[0026] (5) Dissolving the gastric soluble film coating premix in water, adding hydrochloric acid to adjust the pH value to 1-4 after evenly dispersing, and then adding polyethylene glycol and stirring evenly to obtain a color coating solution; placing the saxagliptin metformin sustained-release tablet base into a coating machine for coating, thereby obtaining the saxagliptin metformin sustained-release tablet.

[0027] Preferably, the particle size of the silica pellet core is 1-2 mm, and the particle size of the metformin hydrochloride pellet is 0.3-3 mm.

[0028] Preferably, in parts by weight, the amount of water used in step (1) is 1000-4000 parts, the amount of ethanol used in step (3) is 100-300 parts, and the water used in the preparation method of the present invention is purified water.

[0029] Preferably, in step (2), the coating flow rate is 5 g / min-20 g / min, the atomization pressure is 0.5 bar-2.0 bar, and during the coating process, 1 / 4, 1 / 2, and 3 / 4 of the coating solution are used to determine the content of the saxagliptin microcapsules, a content / time curve is drawn, and the coating endpoint is determined based on the curve results.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] (1) The present invention adopts extrusion spheronization to prepare metformin hydrochloride pellets, and adopts fluidized coating to prepare saxagliptin pellets. The metformin hydrochloride pellets are granulated by a granulator to make the particle size close to that of the saxagliptin pellets. The two pellets with similar particle sizes are easy to mix evenly, and the tablet weight can be adjusted according to the content of the total mixed particles, which fundamentally solves the problem of inaccurate dosage caused by low saxagliptin content. The saxagliptin metformin sustained-release tablets prepared by the method of the present invention have accurate dosage, good saxagliptin uniformity, and are equal to or even better in quality than the reference preparation of saxagliptin metformin sustained-release tablets.

[0032] (2) The present invention dissolves saxagliptin monohydrate in water to form a saxagliptin coating solution. At this time, saxagliptin monohydrate loses a molecule of water to become saxagliptin. Saxagliptin is unstable and easily causes the related substances in the finished product to exceed the limit. The present invention acidifies saxagliptin to form saxagliptin hydrochloride. Saxagliptin hydrochloride is more stable under acidic conditions. The present invention uses a color coating acidified with hydrochloric acid to coat the substrate, which further improves the stability of saxagliptin. The addition of polyethylene glycol to the color coating improves the density and film-forming properties of the coating, which has a good guarantee for the stability of the substrate. At the same time, the addition can reduce the generation of foam and shorten the preparation time of the coating solution.

[0033] (3) The preparation method of the present invention is different from the traditional process. Compared with the original preparation, the original process is to coat the metformin hydrochloride tablet core with three layers of isolation layer, drug layer and color layer. The process time is long and the dosage accuracy of saxagliptin is a huge problem. The method of the present invention adopts the method of extrusion spheronization to prepare metformin hydrochloride microcapsules and fluidized coating to prepare saxagliptin microcapsules. It can be produced by multiple lines, with short process time, simple process, good continuity and high degree of mechanization, which is more suitable for industrial production. The method of the present invention shortens the production time of the original preparation from 10 days to 5 days, significantly improving the production efficiency. DETAILED DESCRIPTION

[0034] The present invention is further described below with reference to the examples. If no specific conditions are specified in the examples, the experiments are carried out according to conventional conditions or conditions recommended by the manufacturer. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0035] Example 1

[0036] The raw material composition of the saxagliptin metformin sustained-release tablets is shown in Table 1 in parts by weight (prescription dosage for 1000 tablets).

[0037] The preparation method of the saxagliptin metformin sustained-release tablets comprises the following steps:

[0038] (1) Evenly dispersing saxagliptin monohydrate, hypromellose and talc in 3000 parts of purified water to obtain a saxagliptin coating solution, and acidifying the saxagliptin coating solution with hydrochloric acid to control the pH value to 3;

[0039] (2) Put silica pellets with a particle size of 1.5 mm into the fluidized bed, preheat the pellets to 40°C, spray the acidified saxagliptin coating solution into the fluidized bed after preheating, set the flow rate to 10 g / min for coating, and simultaneously set the atomization pressure to 1.0 bar. Use 1 / 4, 1 / 2, and 3 / 4 of the coating solution to determine the content of saxagliptin pellets, draw a content / time curve, and determine the coating endpoint based on the curve results. When the coating is completed, saxagliptin pellets are obtained;

[0040] (3) Ethyl cellulose was dissolved in 250 parts of ethanol, and then triethyl citrate was added and stirred evenly. The obtained solution was evenly sprayed into metformin hydrochloride in a wet granulator using a spray gun to prepare a wet material. Metformin hydrochloride micropellets with a particle size of 1.5 mm were prepared using an extrusion spheronizer, and then dried for later use;

[0041] (4) Evenly mixing the metformin hydrochloride pellets, saxagliptin pellets, microcrystalline cellulose and magnesium stearate, and tableting to obtain saxagliptin metformin sustained-release tablets;

[0042] (5) Dissolve the gastric soluble film coating premix in purified water, add hydrochloric acid to adjust the pH value to 3 after evenly dispersing, then add polyethylene glycol and stir evenly to obtain a color coating solution; put the saxagliptin metformin sustained-release tablet base into a coating machine for coating, and obtain the saxagliptin metformin sustained-release tablet.

[0043] Example 2

[0044] The raw material composition and dosage of the saxagliptin metformin sustained-release tablets (prescription dosage for 1000 tablets) are shown in Table 1.

[0045] The preparation method of the saxagliptin metformin sustained-release tablets comprises the following steps:

[0046] (1) Evenly dispersing saxagliptin monohydrate, hypromellose and talc in 2000 parts of purified water to obtain a saxagliptin coating solution, and acidifying the saxagliptin coating solution with hydrochloric acid to control the pH value to be 1;

[0047] (2) Put the silica pellets with a particle size of 2 mm into the fluidized bed, preheat the pellets to 40°C, spray the acidified saxagliptin coating solution into the fluidized bed after preheating, set the flow rate to 10 g / min for coating, and simultaneously set the atomization pressure to 1.0 bar. Use 1 / 4, 1 / 2, and 3 / 4 of the coating solution to determine the content of the saxagliptin micropellets, draw a content / time curve, and determine the coating endpoint based on the curve results. When the coating is completed, the saxagliptin micropellets are obtained;

[0048] (3) Ethyl cellulose was dissolved in 200 parts of ethanol, and then triethyl citrate was added and stirred evenly. The obtained solution was evenly sprayed into metformin hydrochloride in a wet granulator using a spray gun to prepare a wet material. Metformin hydrochloride micropellets with a particle size of 1.5 mm were prepared using an extrusion spheronizer, and then dried for later use;

[0049] (4) Evenly mixing the metformin hydrochloride pellets, saxagliptin pellets, microcrystalline cellulose and magnesium stearate, and tableting to obtain saxagliptin metformin sustained-release tablets;

[0050] (5) Dissolving the gastric soluble film coating premix in purified water, adding hydrochloric acid to adjust the pH value to 1 after evenly dispersing, and then adding polyethylene glycol and stirring evenly to obtain a color coating solution; placing the saxagliptin metformin sustained-release tablet base into a coating machine for coating, thereby obtaining the saxagliptin metformin sustained-release tablet.

[0051] Example 3

[0052] The raw material composition and dosage of the saxagliptin metformin sustained-release tablets (prescription dosage for 1000 tablets) are shown in Table 1.

[0053] The preparation method of the saxagliptin metformin sustained-release tablets comprises the following steps:

[0054] (1) Evenly dispersing saxagliptin monohydrate, hypromellose and talc in 3500 parts of purified water to obtain a saxagliptin coating solution, and acidifying the saxagliptin coating solution with hydrochloric acid to control the pH value to 4;

[0055] (2) Put the silica pellets with a particle size of 1 mm into the fluidized bed, preheat the pellets to 40°C, spray the acidified saxagliptin coating solution into the fluidized bed after preheating, set the flow rate to 10 g / min for coating, and simultaneously set the atomization pressure to 1.0 bar. Use 1 / 4, 1 / 2, and 3 / 4 of the coating solution to determine the content of the saxagliptin micropellets, draw a content / time curve, and determine the coating endpoint based on the curve results. When the coating is completed, the saxagliptin micropellets are obtained;

[0056] (3) Ethyl cellulose was dissolved in 300 parts of ethanol, and then triethyl citrate was added and stirred evenly. The obtained solution was evenly sprayed into metformin hydrochloride in a wet granulator using a spray gun to prepare a wet material, and metformin hydrochloride micropellets with a particle size of 1.5 mm were prepared using an extrusion spheronizer, and then dried for later use;

[0057] (4) Evenly mixing the metformin hydrochloride pellets, saxagliptin pellets, microcrystalline cellulose and magnesium stearate, and tableting to obtain saxagliptin metformin sustained-release tablets;

[0058] (5) Dissolve the gastric soluble film coating premix in purified water, add hydrochloric acid to adjust the pH value to 4 after evenly dispersing, then add polyethylene glycol and stir evenly to obtain a color coating solution; put the saxagliptin metformin sustained-release tablet base into a coating machine for coating, and obtain the saxagliptin metformin sustained-release tablet.

[0059] Table 1 Raw material composition of Saxagliptin Metformin Sustained Release Tablets of Example 1-3 in parts by weight (prescription dosage for 1000 tablets)

[0060]

[0061] Example 4

[0062] The saxagliptin metformin sustained-release tablets use the same raw materials and preparation method as in Example 1, except that the particle size of the metformin hydrochloride pellets is 0.3 mm.

[0063] Example 5

[0064] The saxagliptin metformin sustained-release tablets use the same raw materials and preparation method as in Example 1, except that the particle size of the metformin hydrochloride pellets is 3 mm.

[0065] Example 6

[0066] The saxagliptin metformin sustained-release tablets include saxagliptin pellets, metformin hydrochloride pellets and color coating;

[0067] The saxagliptin pellets include the following raw materials in parts by weight: 2.65 parts of saxagliptin monohydrate, 20 parts of silicon dioxide pellet cores, 1 part of hypromellose, 0.1 parts of talc, and 10 parts of hydrochloric acid;

[0068] The metformin hydrochloride pellets include the following raw materials in parts by weight: 500 parts of metformin hydrochloride, 2 parts of ethyl cellulose, and 2 parts of triethyl citrate;

[0069] The color coating comprises the following raw materials in parts by weight: 200 parts of gastric soluble film coating premix, 10 parts of hydrochloric acid, and 10 parts of polyethylene glycol;

[0070] It also includes auxiliary materials: 75 parts of microcrystalline cellulose and 5 parts of magnesium stearate.

[0071] The preparation method of the saxagliptin metformin sustained-release tablets comprises the following steps:

[0072] (1) Evenly dispersing saxagliptin monohydrate, hypromellose and talc in 4000 parts of purified water to obtain a saxagliptin coating solution, and acidifying the saxagliptin coating solution with hydrochloric acid to control the pH value to 4;

[0073] (2) Put the silica pellets with a particle size of 1.5 mm into the fluidized bed, preheat the pellets to 40°C, spray the acidified saxagliptin coating solution into the fluidized bed after preheating, set the flow rate to 5 g / min for coating, and simultaneously set the atomization pressure to 0.5 bar. Use 1 / 4, 1 / 2, and 3 / 4 of the coating solution to determine the content of the saxagliptin micropellets, draw a content / time curve, and determine the coating endpoint based on the curve results. When the coating is completed, the saxagliptin micropellets are obtained;

[0074] (3) Ethyl cellulose was dissolved in 250 parts of ethanol, and then triethyl citrate was added and stirred evenly. The obtained solution was evenly sprayed into metformin hydrochloride in a wet granulator using a spray gun to prepare a wet material. Metformin hydrochloride micropellets with a particle size of 1.5 mm were prepared using an extrusion spheronizer, and then dried for later use;

[0075] (4) Evenly mixing the metformin hydrochloride pellets, saxagliptin pellets, microcrystalline cellulose and magnesium stearate, and tableting to obtain saxagliptin metformin sustained-release tablets;

[0076] (5) Dissolve the gastric soluble film coating premix in purified water, add hydrochloric acid to adjust the pH value to 4 after evenly dispersing, then add polyethylene glycol and stir evenly to obtain a color coating solution; put the saxagliptin metformin sustained-release tablet base into a coating machine for coating, and obtain the saxagliptin metformin sustained-release tablet.

[0077] Example 7

[0078] The saxagliptin metformin sustained-release tablets include saxagliptin pellets, metformin hydrochloride pellets and color coating:

[0079] The saxagliptin pellets include the following raw materials in parts by weight: 5.29 parts of saxagliptin monohydrate, 50 parts of silicon dioxide pellet cores, 1 part of hypromellose, 0.2 parts of talc, and 40 parts of hydrochloric acid;

[0080] The metformin hydrochloride pellets include the following raw materials in parts by weight: 1000 parts of metformin hydrochloride, 4 parts of ethyl cellulose, and 4 parts of triethyl citrate;

[0081] The color coating comprises the following raw materials in parts by weight: 500 parts of gastric soluble film coating premix, 40 parts of hydrochloric acid, and 40 parts of polyethylene glycol;

[0082] It also includes auxiliary materials: 150 parts of microcrystalline cellulose and 10 parts of magnesium stearate.

[0083] The preparation method of the saxagliptin metformin sustained-release tablets comprises the following steps:

[0084] (1) Evenly dispersing saxagliptin monohydrate, hypromellose and talc in 1000 parts of purified water to obtain a saxagliptin coating solution, and acidifying the saxagliptin coating solution with hydrochloric acid to control the pH value to be 1;

[0085] (2) Put silica pellets with a particle size of 1.5 mm into the fluidized bed, preheat the pellets to 40°C, spray the acidified saxagliptin coating solution into the fluidized bed after preheating, set the flow rate to 20 g / min for coating, and simultaneously set the atomization pressure to 2.0 bar. Use 1 / 4, 1 / 2, and 3 / 4 of the coating solution to determine the content of saxagliptin pellets, draw a content / time curve, and determine the coating endpoint based on the curve results. When the coating is completed, saxagliptin pellets are obtained;

[0086] (3) Ethyl cellulose was dissolved in 100 parts of ethanol, and then triethyl citrate was added and stirred evenly. The obtained solution was evenly sprayed into metformin hydrochloride in a wet granulator using a spray gun to prepare a wet material, and metformin hydrochloride micropellets with a particle size of 1.5 mm were prepared using an extrusion spheronizer, and then dried for later use;

[0087] (4) Evenly mixing the metformin hydrochloride pellets, saxagliptin pellets, microcrystalline cellulose and magnesium stearate, and tableting to obtain saxagliptin metformin sustained-release tablets;

[0088] (5) Dissolving the gastric soluble film coating premix in purified water, adding hydrochloric acid to adjust the pH value to 1 after evenly dispersing, and then adding polyethylene glycol and stirring evenly to obtain a color coating solution; placing the saxagliptin metformin sustained-release tablet base into a coating machine for coating, thereby obtaining the saxagliptin metformin sustained-release tablet.

[0089] Comparative Example 1

[0090] The raw material composition and dosage of the saxagliptin metformin sustained-release tablets are similar to those of Example 1, except that the color coating is only a gastric-soluble film coating premix, and does not contain hydrochloric acid and polyethylene glycol.

[0091] The preparation method is as described in Example 1, except that, in step (5), the gastric soluble film coating premix is ​​dissolved in purified water to obtain a color coating solution; the saxagliptin metformin sustained-release tablet base is placed in a coating machine for coating, thereby obtaining the saxagliptin metformin sustained-release tablet.

[0092] Comparative Example 2

[0093] The raw material composition of the saxagliptin metformin sustained-release tablets is as follows in parts by weight (prescription dosage for 1000 tablets):

[0094] Metformin hydrochloride pellets: 1000 parts of metformin hydrochloride, 5 parts of ethyl cellulose, 6 parts of triethyl citrate;

[0095] Isolation layer: 100 parts of hydroxypropyl cellulose, 15 parts of talc, 3 parts of hydrochloric acid;

[0096] Saxagliptin coating solution: 5.29 parts of saxagliptin monohydrate, 2 parts of hypromellose, 0.35 parts of talc, 30 parts of hydrochloric acid;

[0097] Excipients: 200 parts of microcrystalline cellulose, 10 parts of magnesium stearate;

[0098] Color coating: 450 parts of gastric soluble film coating premix, 30 parts of hydrochloric acid, and 25 parts of polyethylene glycol.

[0099] The preparation method is as follows:

[0100] (1) Evenly dispersing saxagliptin monohydrate, hypromellose and talc in 3000 parts of purified water to obtain a saxagliptin coating solution, and acidifying the saxagliptin coating solution with hydrochloric acid to control the pH value to 3;

[0101] (2) Dissolve ethyl cellulose in 250 parts of ethanol, then add triethyl citrate and stir evenly, spray the obtained solution evenly into metformin hydrochloride in a wet granulator with a spray gun to prepare a wet material, use an extrusion spheronizer to prepare metformin hydrochloride micropellets, and dry them for later use;

[0102] (3) Dispersing hydroxypropyl cellulose and talc evenly in 300 parts of purified water, adding hydrochloric acid to adjust the pH value to 3 after the dispersion is uniform, to obtain an isolation layer coating solution;

[0103] (4) Putting the metformin hydrochloride pellets into the fluidized bed, preheating the pellets to 40°C, spraying the isolation layer coating liquid after the preheating is completed, coating, and obtaining isolation pellets; after the isolation pellets are preheated, starting the saxagliptin drug coating, setting the flow rate to 10 g / min for coating, and simultaneously setting the atomization pressure to 1.0 bar, using 1 / 4, 1 / 2, and 3 / 4 of the coating liquid to measure the content of the saxagliptin pellets, respectively, drawing a content / time curve, and determining the coating endpoint based on the curve results, to obtain metformin hydrochloride saxagliptin pellets;

[0104] (5) Evenly mixing the metformin hydrochloride and saxagliptin micropellets with microcrystalline cellulose and magnesium stearate, and tableting to obtain saxagliptin metformin sustained-release tablets;

[0105] (6) Dissolve the gastric soluble film coating premix in purified water, add hydrochloric acid to adjust the pH value to 3 after evenly dispersing, then add polyethylene glycol and stir evenly to obtain a color coating solution; put the saxagliptin metformin sustained-release tablet base into a coating machine for coating, and obtain the saxagliptin metformin sustained-release tablet.

[0106] Comparative Example 3

[0107] The saxagliptin metformin sustained-release tablets use the same raw materials and preparation method as in Example 1, except that the particle size of the silica pellet core is 1.5 mm, and the particle size of the metformin hydrochloride pellet is 0.1 mm.

[0108] Comparative Example 4

[0109] The saxagliptin metformin sustained-release tablets use the same raw materials and preparation method as in Example 1, except that the particle size of the silica pellet core is 1.5 mm, and the particle size of the metformin hydrochloride pellets is 5 mm.

[0110] Comparative Example 5

[0111] The saxagliptin metformin sustained-release tablets use the same raw materials and preparation method as in Example 1, except that the color coating includes a gastric-soluble film coating premix and hydrochloric acid, and does not contain polyethylene glycol.

[0112] Comparative Example 6

[0113] Commercially available saxagliptin metformin sustained-release tablets (Ⅰ) original formulation - AstraZeneca AB, trade name Anlig, batch number: NB3537.

[0114] Test Example 1

[0115] The content uniformity of saxagliptin was investigated for the preparations of Examples 1-3 and Comparative Examples 1, 2, and 6 according to the content uniformity test method of the Chinese Pharmacopoeia. The test results are shown in Table 2.

[0116] Table 2 Investigation on the uniformity of saxagliptin content

[0117]

[0118] The content uniformity data of the saxagliptin of Examples 1-3, Comparative Examples 1, 2, and 6 in the saxagliptin metformin sustained-release tablets prepared by the present invention are known according to the "Technical Guidance for the Study of Mixing Uniformity and Unit Uniformity of Controlled Dosages of Chemical Oral Solid Preparations", and all test results meet the requirements. However, the result of A+2.2S in Comparative Example 2 is 13.53, which is close to being unqualified, because the hardness of the metformin hydrochloride pellets prepared by extrusion spheronization is relatively low, and the pellets rupture when using fluidized bed coating, resulting in a poor result of the content uniformity of the saxagliptin layer. The results of Examples 1-3 and Comparative Example 1 are all better than the reference preparation, because the saxagliptin pellets with uniform content prepared in the fluidized bed can be converted to a dose according to the content data obtained by the intermediate product inspection during the tableting process, thereby achieving a uniform dose effect.

[0119] It can be concluded from the above data that the saxagliptin metformin sustained-release tablets prepared by the present invention have accurate dosage, more uniform saxagliptin content than the reference preparation, and obvious advantages in accurate dosage.

[0120] Test Example 2

[0121] In accordance with the stability test guidelines of the Chinese Pharmacopoeia, accelerated tests (40°C ± 2°C, RH 75% ± 5%) were performed on the preparations of Examples 1-3 and Comparative Examples 1, 2, 5, and 6. The test results are shown in Tables 3-9.

[0122] Table 3 6-month data of the accelerated test (40°C ± 2°C, RH 75% ± 5%) of Example 1

[0123] Table 4 6-month data of accelerated test (40°C ± 2°C, RH 75% ± 5%) of Example 2

[0124]

[0125] Table 5 6-month data of the accelerated test (40°C ± 2°C, RH 75% ± 5%) of Example 3

[0126]

[0127] Table 6 6-month data of accelerated test (40℃±2℃, RH75%±5%) of comparative example 1

[0128]

[0129] Table 7 Comparative Example 2 Accelerated Test (40℃±2℃, RH75%±5%) 6-month data

[0130]

[0131] Table 8 Comparative Example 5 Accelerated Test (40℃±2℃, RH75%±5%) 6-month data

[0132]

[0133] Table 9 Comparative Example 6 Accelerated Test (40℃±2℃, RH75%±5%) 6 Months Data

[0134] It can be seen from the test results in Table 3-9 that the results of the 6-month stability test (40°C ± 2°C, RH 75% ± 5%) of Example 1, Example 2, and Example 3 are better than those of the original preparation. This is because saxagliptin is prepared into saxagliptin pellets, and the structure of the saxagliptin pellets is relatively independent compared with the original preparation, so that the formed saxagliptin hydrochloride can be stored stably for a long time.

[0135] The results of the 6-month stability test (40°C ± 2°C, RH 75% ± 5%) of Examples 1, 2, and 3 are better than those of Comparative Example 1. This is because saxagliptin hydrochloride itself has poor stability, but can be stored stably for a long time under acidic conditions, so adjusting the pH of the coating layer helps to improve the stability of the preparation.

[0136] The results of the 6-month stability test (40°C ± 2°C, RH 75% ± 5%) of Example 1, Example 2, and Example 3 were better than those of Comparative Example 2. There was no obvious benefit in coating the saxagliptin layer using metformin hydrochloride pellets as the base.

[0137] The results of the 6-month stability test of the accelerated test (40°C ± 2°C, RH75% ± 5%) of Example 1, Example 2, and Example 3 are better than those of Comparative Example 5. In the process of preparing the coating solution, foam will appear in Comparative Example 5. It is found that the pH of the foam is quite different from that of the coating solution. The lower pH value in the foam will affect the coating quality during the coating process, and the foam is more corrosive to the equipment and has a greater impact on the equipment. It can be seen that in the process of preparing the coating solution, adding polyethylene glycol can reduce the generation of foam and because the coating powder contains polyethylene glycol, other substances will not be introduced. Adding polyethylene glycol can make the coating solution more uniformly prepared and the solid content more evenly distributed. Adding polyethylene glycol can also shorten the preparation time of the coating solution, reduce the cost of commercial production and improve efficiency.

[0138] Test Example 3

[0139] The mixing uniformity of the total mixed particles of Examples 4 and 5 and Comparative Examples 3 and 4 was investigated, and the test results are shown in Table 10.

[0140] Table 10 Investigation on the mixing uniformity of the total mixed granules of saxagliptin metformin sustained-release tablets

[0141]

[0142] According to the mixing uniformity results of the total mixed particles of saxagliptin metformin sustained-release tablets, it can be seen that the mixing uniformity results of the saxagliptin content and metformin hydrochloride content of Examples 4 and 5, Comparative Examples 3 and 4 all meet the requirements. Example 4 prepares a smaller metformin hydrochloride pellet, while Example 5 prepares a larger one, but overall, the particle size of the silica attached to the saxagliptin coating is close, and the two pellets with similar particle sizes are easy to mix. Although the gap between the saxagliptin pellets prepared in Comparative Examples 3 and 4 and the metformin hydrochloride pellets is larger than that of Examples 4 and 5, they also meet the requirements.

[0143] In summary, it can be seen that the saxagliptin metformin sustained-release tablets prepared by the present invention have obvious advantages over the original preparation.

Claims

1. A saxagliptin metformin sustained-release tablet, characterized in that: The invention comprises saxagliptin pellets, metformin hydrochloride pellets and color coating; the saxagliptin pellets comprise the following raw materials: saxagliptin monohydrate, silicon dioxide pellet core, hypromellose, talcum powder and hydrochloric acid; the metformin hydrochloride pellets comprise the following raw materials: metformin hydrochloride, ethyl cellulose and triethyl citrate; the color coating comprises the following raw materials: gastric soluble film coating premix, hydrochloric acid and polyethylene glycol; The saxagliptin pellets include the following raw materials in parts by weight: 2.65-5.29 parts of saxagliptin monohydrate, 20-100 parts of silicon dioxide pellet cores, 1-3 parts of hypromellose, 0.1-0.5 parts of talc, and 10-40 parts of hydrochloric acid; The metformin hydrochloride pellets include the following raw materials in parts by weight: 500-1000 parts of metformin hydrochloride, 2-6 parts of ethyl cellulose, and 2-8 parts of triethyl citrate; The color coating comprises the following raw materials in parts by weight: 200-500 parts of gastric soluble film coating premix, 10-40 parts of hydrochloric acid, and 10-40 parts of polyethylene glycol; The saxagliptin metformin sustained-release tablets also include microcrystalline cellulose and magnesium stearate; in parts by weight, the amount of microcrystalline cellulose is 75-300 parts, and the amount of magnesium stearate is 5-15 parts; The preparation method of the saxagliptin metformin sustained-release tablets comprises the following steps: (1) uniformly dispersing saxagliptin monohydrate, hypromellose and talc in water to obtain a saxagliptin coating solution, and acidifying the saxagliptin coating solution with hydrochloric acid; (2) placing the silica pellet cores into a fluidized bed, spraying the acidified saxagliptin coating solution into the cores, and coating the cores to obtain saxagliptin pellets; (3) Dissolve ethyl cellulose in ethanol, then add triethyl citrate and stir evenly, add to metformin hydrochloride to prepare a wet material, and use an extrusion spheronizer to prepare metformin hydrochloride microcapsules; (4) Evenly mixing the metformin hydrochloride pellets, saxagliptin pellets, microcrystalline cellulose and magnesium stearate, and tableting to obtain saxagliptin metformin sustained-release tablets; (5) dissolving the gastric soluble film coating premix in water, adding hydrochloric acid to adjust the pH value after evenly dispersing, and then adding polyethylene glycol and stirring evenly to obtain a color coating solution; placing the saxagliptin metformin sustained-release tablet base into a coating machine for coating, thereby obtaining the saxagliptin metformin sustained-release tablet; The particle size of the silica pellet core is 1-2 mm, and the particle size of the metformin hydrochloride pellet is 0.3-3 mm.

2. A method for preparing the saxagliptin metformin sustained-release tablets according to claim 1, characterized in that: The following steps are involved: (1) uniformly dispersing saxagliptin monohydrate, hypromellose and talc in water to obtain a saxagliptin coating solution, and acidifying the saxagliptin coating solution with hydrochloric acid; (2) placing the silica pellet cores into a fluidized bed, spraying the acidified saxagliptin coating solution into the cores, and coating the cores to obtain saxagliptin pellets; (3) Dissolve ethyl cellulose in ethanol, then add triethyl citrate and stir evenly, add to metformin hydrochloride to prepare a wet material, and use an extrusion spheronizer to prepare metformin hydrochloride microcapsules; (4) Evenly mixing the metformin hydrochloride pellets, saxagliptin pellets, microcrystalline cellulose and magnesium stearate, and tableting to obtain saxagliptin metformin sustained-release tablets; (5) Dissolving the gastric soluble film coating premix in water, adding hydrochloric acid to adjust the pH value after evenly dispersing, and then adding polyethylene glycol and stirring evenly to obtain a color-coated coating solution; placing the saxagliptin metformin sustained-release tablet base into a coating machine for coating, thereby obtaining the saxagliptin metformin sustained-release tablet.

3. The method for preparing the saxagliptin metformin sustained-release tablets according to claim 2, characterized in that: In step (1), the pH value of the acidification treatment is 1-4.

4. The method for preparing the saxagliptin metformin sustained-release tablets according to claim 2, characterized in that: In step (5), hydrochloric acid is added to adjust the pH value to 1-4.

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