Small sitagliptin-metformin sustained release tablet and preparation method thereof

Abstract

The invention discloses a small sitagliptin-metformin sustained release tablet and a preparation method thereof, and belongs to the technical field of medical products, the sitagliptin-metformin sustained release tablet sequentially comprises a sustained release tablet core, an isolation layer, a quick release layer and an outer coating from inside to outside; the sustained release tablet core comprises metformin, resistant starch, microcrystalline cellulose and sodium bicarbonate; the isolating layer comprises an enteric coating. The sustained-release tablet core is coated with the enteric coating, so that the dissolution property is greatly reduced under the acidic condition in the stomach, the stimulation of metformin to the stomach is reduced, and the comfort level of the stomach is improved; and the metformin is gradually released in intestines. The product is small in size and weight, the swallowing experience is improved, and the situation that swallowing is difficult is reduced. The resistant starch and the microcrystalline cellulose have a slow release effect, promote intestinal tract movement and improve the comfort of intestinal tracts; meanwhile, lactic acid rise caused by metformin accumulation can be absorbed.

Description

Technical Field

[0001] The present invention relates to the technical field of medical products, and in particular to a small-sized sitagliptin-metformin sustained-release tablet and a preparation method thereof. Background Art

[0002] Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of drugs developed to treat or improve glycemic control in patients with type 2 diabetes, primarily sitagliptin. Metformin tablets are used for type 2 diabetes that is unresponsive to diet and exercise alone, particularly in obese patients with type 2 diabetes.

[0003] Sitagliptin-Metformin Extended-Release Tablets, composed of sitagliptin phosphate and metformin hydrochloride, are a combination preparation for the treatment of type 2 diabetes. Currently, sitagliptin is coated in a suspension around the core of metformin extended-release tablets, achieving rapid release of sitagliptin and slow release of metformin; this results in rapid onset of action and long-term maintenance of blood sugar stability. Metformin is slowly released in the intestines, which can cause gastrointestinal side effects such as stomach discomfort and diarrhea. Miniaturized sitagliptin-metformin extended-release tablets are easier to swallow, reducing patients' resistance. Summary of the Invention

[0004] In response to the above technical problems existing in the prior art, the present invention provides a small-sized sitagliptin-metformin sustained-release tablet and a preparation method thereof, which can reduce gastrointestinal discomfort.

[0005] The present invention discloses a small-sized sitagliptin-metformin sustained-release tablet, which comprises a sustained-release tablet core, an isolation layer, a quick-release layer and an outer coating from the inside out; the sustained-release tablet core comprises metformin, resistant starch, microcrystalline cellulose and sodium bicarbonate; and the isolation layer comprises an enteric coating.

[0006] Preferably, the immediate-release layer comprises sitagliptin, hypromellose and croscarmellose.

[0007] Preferably, the release pH range of the enteric coating is 5.8-6.5; and the outer coating is a gastric-soluble coating.

[0008] Preferably, based on 1000 parts, the sustained-release tablet core comprises the following ingredients:

[0009] 500-1000g metformin hydrochloride, 50-100g resistant starch, 50-90g microcrystalline cellulose, 1-5g sodium bicarbonate, 1-5g magnesium stearate, 5-10g polyvinylpyrrolidone, 1-3g micropowdered silica and 0.5-2g silicon dioxide.

[0010] Preferably, the enteric coating comprises the following ingredients:

[0011] 4-6g acrylic resin No. II, 1-3g hydroxypropyl methylcellulose phthalate, 2g hydroxypropyl methylcellulose, 1g polyethylene glycol 4000.

[0012] Preferably, the immediate-release layer comprises the following ingredients: 45-50 g sitagliptin, 6-10 g hydroxypropyl methylcellulose, 0.2-0.5 g talc, and 0.2-0.5 g silicon dioxide.

[0013] Preferably, the ingredients of the sustained-release tablet core include: 500g of metformin hydrochloride, 80g of resistant starch, 50g of microcrystalline cellulose, 1g of sodium bicarbonate, 8g of polyvinyl pyrrolidone, 1g of micropowdered silica gel, and 0.5g of silicon dioxide;

[0014] The enteric coating comprises the following ingredients: acrylic resin No. II 4 g, hydroxypropyl methylcellulose phthalate 1 g, hydroxypropyl methylcellulose 2 g, and polyethylene glycol 4000 1 g;

[0015] The immediate-release layer includes the following ingredients: sitagliptin 45 g, hydroxypropyl methylcellulose 8 g, talc 0.5 g, and silicon dioxide 0.2 g.

[0016] Preferably, the ingredients of the sustained-release tablet core include: 1000 g of metformin hydrochloride, 50 g of resistant starch, 60 g of microcrystalline cellulose, 3 g of sodium bicarbonate, 10 g of polyvinyl pyrrolidone, 3 g of micropowdered silica gel, 1 g of silicon dioxide, and 5 g of magnesium stearate;

[0017] The enteric coating comprises the following ingredients: acrylic resin No. II 6 g, hydroxypropyl methylcellulose phthalate 3 g, hydroxypropyl methylcellulose 2 g, and polyethylene glycol 4000 1 g;

[0018] The immediate-release layer includes the following ingredients: sitagliptin 50 g, hydroxypropyl methylcellulose 6 g, talc 0.3 g, and silicon dioxide 0.5 g.

[0019] Preferably, the ingredients of the sustained-release tablet core include: 800g of metformin hydrochloride, 100g of resistant starch, 90g of microcrystalline cellulose, 5g of sodium bicarbonate, 6g of polyvinyl pyrrolidone, 1g of micropowdered silica gel, 2g of silicon dioxide, and 1g of magnesium stearate;

[0020] The enteric coating comprises the following ingredients: acrylic resin No. II 5 g, hydroxypropyl methylcellulose phthalate 2 g, hydroxypropyl methylcellulose 2 g, polyethylene glycol 4000 1 g;

[0021] The immediate-release layer includes the following ingredients: sitagliptin 48 g, hydroxypropyl methylcellulose 8 g, talc 0.4 g, and silicon dioxide 0.3 g.

[0022] The present invention also provides a method for preparing the above-mentioned small-sized sitagliptin-metformin sustained-release tablets, comprising the following steps:

[0023] After mixing the components of the sustained-release tablet core, granulating the mixture using a dry granulator to obtain the sustained-release tablet core;

[0024] Dissolve the components of the enteric coating in 75-95% ethanol solution to obtain a first coating solution;

[0025] Using a coating machine, coating the first coating liquid on the outside of the sustained-release tablet core to obtain a first crude product;

[0026] Add water to the ingredients of the immediate-release layer and stir thoroughly to obtain a second coating solution;

[0027] Using a coating machine, coating the outside of the first crude product with the second coating liquid to obtain a second crude product;

[0028] adding water to the gastric soluble coating ingredients and stirring to obtain a third coating solution;

[0029] The third coating liquid is coated on the outside of the second crude product by a coating machine to obtain small sitagliptin-metformin sustained-release tablets.

[0030] Compared with the prior art, the present invention has the following beneficial effects: the sustained-release tablet core is coated in an enteric coating, and under the acidic conditions of the stomach, the solubility is significantly reduced, reducing the irritation of metformin to the stomach and improving gastric comfort; metformin is gradually released in the intestine. The product of the present invention is small in size and weight, improving the swallowing experience and reducing the difficulty in swallowing. Resistant starch and microcrystalline cellulose have a sustained-release effect, while promoting intestinal peristalsis and improving intestinal comfort; at the same time, they can absorb the increase in lactic acid caused by the accumulation of metformin. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is a flow chart of the preparation method of the small-sized sitagliptin-metformin sustained-release tablets of the present invention;

[0032] Figure 2 This is a curve chart of the average scores of the gastrointestinal comfort survey. DETAILED DESCRIPTION

[0033] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts shall fall within the scope of protection of the present invention.

[0034] The present invention is described in further detail below with reference to the accompanying drawings:

[0035] A first aspect of the present invention provides a small-sized sitagliptin-metformin sustained-release tablet comprising, from the inside out, a sustained-release tablet core, a separating layer, an immediate-release layer, and an outer coating. The sustained-release tablet core comprises metformin, sodium bicarbonate, microcrystalline cellulose, and resistant starch. The separating layer is an enteric coating. The immediate-release layer comprises sitagliptin, hypromellose, and cross-linked hydroxymethylcellulose.

[0036] The sustained-release tablet core is coated in an enteric coating. Under the acidic conditions of the stomach, the dissolution rate is significantly reduced, reducing the irritation of metformin to the stomach and improving gastric comfort; metformin is gradually released in the intestine. The product of the present invention is small in size and weight, improving the swallowing experience and reducing the difficulty in swallowing. Resistant starch and microcrystalline cellulose have a sustained-release effect, while promoting intestinal peristalsis and improving intestinal comfort; at the same time, they can absorb the increase in lactic acid caused by the accumulation of metformin.

[0037] More specifically, the sustained-release core tablet may further comprise any one of the following ingredients: polyvinylpyrrolidone (PVP), micro-powdered silica gel, and silicon dioxide. The immediate-release layer may further comprise talc, silicon dioxide, and an antioxidant.

[0038] The release pH range of the enteric coating is 5.8-6.5. The outer coating is a gastric soluble coating.

[0039] Specifically, based on 1000 portions, the ingredients of each layer in the small sitagliptin-metformin sustained-release tablets are shown in Table 1. Each portion may contain 1-3 tablets.

[0040] Table 1

[0041]

[0042] The preparation method of small-sized sitagliptin-metformin sustained-release tablets comprises the following steps:

[0043] Step 101: After mixing the components of the sustained-release tablet core, granulate the tablet using a dry granulator to obtain a sustained-release tablet core having a thickness of 2-2.5 mm.

[0044] Step 102: Dissolve the components of the enteric coating in 75-95% ethanol solution to obtain a first coating solution.

[0045] Step 103: Use a coating machine to coat the first coating liquid on the outside of the sustained-release tablet core to obtain a first crude product.

[0046] Step 104: Add water to the ingredients of the immediate-release layer and stir thoroughly to obtain a second coating solution.

[0047] Step 105: Use a coating machine to coat the outside of the first crude product with a second coating liquid to obtain a second crude product.

[0048] Step 106: Add the gastric soluble coating ingredients to water and stir to obtain a third coating solution.

[0049] Step 107: Use a coating machine to coat the outer side of the second crude product with the third coating liquid to obtain small sitagliptin-metformin sustained-release tablets.

[0050] Example 1.

[0051] The sustained-release tablet core ingredients include: 500g of metformin hydrochloride, 80g of resistant starch, 50g of microcrystalline cellulose, 1g of sodium bicarbonate, 8g of polyvinyl pyrrolidone, 1g of micropowdered silica gel, and 0.5g of silicon dioxide. After uniform mixing, the mixture is granulated using a dry granulator to obtain 1000 sustained-release tablet cores with a thickness of 2.1mm.

[0052] The enteric coating comprises the following ingredients: 4g of acrylic resin No. II, 1g of hydroxypropyl methylcellulose phthalate, 2g of hydroxypropyl methylcellulose, and 1g of polyethylene glycol 4000. 80ml of 95% ethanol solution is added to obtain a first coating solution. This first coating solution is applied to the outer surface of the sustained-release tablet core using a coating machine to obtain a first crude product. The coating temperature is controlled at 40-45°C. The dissolution pH range of the enteric coating is 5.8-6.5.

[0053] Take the following ingredients for the immediate-release layer: 45g of sitagliptin, 8g of hydroxypropyl methylcellulose, 0.5g of talc, and 0.2g of silicon dioxide. Add 350ml of water and stir thoroughly to obtain a second coating solution. Use a coating machine to coat the second coating solution on the outside of the first crude product to obtain a second crude product.

[0054] 6 g of gastric soluble coating preformed powder was added to 60 ml of water and stirred to obtain a third coating solution. The third coating solution was coated on the outside of the second crude product using a coating machine to obtain small sitagliptin-metformin sustained-release tablets, which were recorded as the first product.

[0055] Example 2.

[0056] The ingredients for the sustained-release tablet core include: 1000g of metformin hydrochloride, 50g of resistant starch, 60g of microcrystalline cellulose, 3g of sodium bicarbonate, 10g of polyvinyl pyrrolidone, 3g of micropowdered silica gel, 1g of silicon dioxide, and 5g of magnesium stearate. After uniform mixing, the mixture is granulated using a dry granulator to obtain 2000 sustained-release tablet cores with a thickness of 2.5mm. Two sustained-release tablets constitute one dose.

[0057] The enteric coating comprises the following ingredients: 6g of acrylic resin No. II, 3g of hydroxypropyl methylcellulose phthalate, 2g of hydroxypropyl methylcellulose, and 1g of polyethylene glycol 4000. 80ml of 75% ethanol solution is added to obtain a first coating solution. This first coating solution is applied to the outer surface of the sustained-release tablet core using a coating machine to obtain a first crude product. The coating temperature is controlled at 40-45°C. The dissolution pH range of the enteric coating is 5.5-6.5.

[0058] Take the following ingredients for the immediate-release layer: 50 g of sitagliptin, 6 g of hydroxypropyl methylcellulose, 0.3 g of talc, and 0.5 g of silicon dioxide. Add 330 ml of water and stir thoroughly to obtain a second coating solution. Use a coating machine to coat the second coating solution on the outside of the first crude product to obtain a second crude product.

[0059] 12 g of gastric soluble coating preformed powder was added to 60 ml of water and stirred to obtain a third coating solution. The third coating solution was coated on the outside of the second crude product using a coating machine to obtain small sitagliptin-metformin sustained-release tablets, which were recorded as the second product.

[0060] Example 3.

[0061] The sustained-release tablet core ingredients include: 800g of metformin hydrochloride, 100g of resistant starch, 90g of microcrystalline cellulose, 5g of sodium bicarbonate, 6g of polyvinylpyrrolidone, 1g of micropowdered silica gel, 2g of silicon dioxide, and 1g of magnesium stearate. After uniform mixing, the mixture is granulated using a dry granulator to obtain 1000 sustained-release tablet cores with a thickness of 2.3mm.

[0062] The enteric coating comprises the following ingredients: 5g of acrylic resin No. II, 2g of hydroxypropyl methylcellulose phthalate, 2g of hydroxypropyl methylcellulose, and 1g of polyethylene glycol 4000. 80ml of 75% ethanol solution is added to obtain a first coating solution. The first coating solution is applied to the outer surface of the sustained-release tablet core using a coating machine to obtain a first crude product. The coating temperature is controlled at 40-45°C. The dissolution pH range of the enteric coating is 6.0-6.5.

[0063] The immediate-release layer contains the following ingredients: 48g of sitagliptin, 8g of hydroxypropyl methylcellulose, 0.4g of talc, and 0.3g of silicon dioxide. Add 330ml of water and stir thoroughly to obtain a second coating solution. This second coating solution is then coated onto the outside of the first crude product using a coating machine to obtain a second crude product.

[0064] 10 g of gastric soluble coating preformed powder was added to 60 ml of water and stirred to obtain a third coating solution. The third coating solution was coated on the outside of the second crude product using a coating machine to obtain small sitagliptin-metformin sustained-release tablets, which were recorded as the third product.

[0065] A phosphate buffer solution of pH 6.5 was added to each product, and the mixture was stirred at 70 rpm at 37° C. Samples were taken at 1-12 hours, and the release rate of metformin was detected by high performance liquid chromatography.

[0066] As shown in Table 2, metformin is released gradually over 12 hours.

[0067] Table 2

[0068] time 1 hour 2 hours 8 hours 12 hours Release rate of the first product (%) 19.01 41.11 89.74 96.8 Second product release (%) 18.25 40.51 88.82 97.9 Second product release (%) 20.61 39.31 88.11 95.7

[0069] A phosphate buffer solution of pH 4.0 was added to each product, and the mixture was stirred at 70 rpm at 37° C. Samples were taken at 1-12 hours, and the release rate of metformin was detected by high performance liquid chromatography.

[0070] As shown in Table 3, the amount of metformin released under acidic conditions within 1 hour is less than 5%, and it is gradually released within 12 hours.

[0071] Table 3

[0072] time 1 hour 2 hours 8 hours 12 hours Release rate of the first product (%) 2.01 19.21 40.51 96.82 Second product release (%) 3.25 18.34 39.34 97.62 Second product release (%) 4.61 20.54 43.64 95.82

[0073] A questionnaire survey was conducted using commercially available sitagliptin-metformin as a control product. Forty-eight patients were recruited and divided equally into four groups, with 12 patients in each group. They took the control product, the first product, the second product, and the third product for four consecutive weeks, and their blood sugar was tested within one hour after taking the product. Patients scored the degree of abdominal pain and bloating according to their own gastrointestinal conditions, as shown in Tables 4 and Figure 2 The scores were averaged. The reference product was commercially available sitagliptin and metformin tablets. The average scores of the first, second, and third products were significantly higher than those of the reference product.

[0074] Table 4

[0075]

[0076] The present invention coats the sustained-release tablet core in an enteric coating. Under the acidic conditions in the stomach, the solubility is greatly reduced, reducing the irritation of metformin to the stomach and improving gastric comfort; metformin is gradually released under the weak acid conditions of pH 5.8-6.5 in the intestine. The product of the present invention has a small volume and weight, which improves the swallowing experience and reduces the difficulty in swallowing. Resistant starch and microcrystalline cellulose are added to the sustained-release tablet core to achieve a sustained-release effect, while promoting intestinal peristalsis, improving intestinal comfort, and reducing intestinal irritation; sodium bicarbonate can absorb the increase in lactic acid caused by the accumulation of metformin.

[0077] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A small-sized sitagliptin-metformin sustained-release tablet, characterized in that: From the inside to the outside, it includes a sustained-release core, a separation layer, a quick-release layer, and an outer coating; The extended-release tablet core includes metformin, resistant starch, microcrystalline cellulose, and sodium bicarbonate; The isolation layer includes an enteric coating.

2. The small-sized sitagliptin-metformin sustained-release tablet according to claim 1, characterized in that: The immediate-release layer includes sitagliptin, hypromellose and cross-linked hydroxymethylcellulose.

3. The small-sized sitagliptin-metformin sustained-release tablet according to claim 1, characterized in that: The release pH range of the enteric coating is: 5.8-6.5; The outer coating is a gastric soluble coating.

4. The small-sized sitagliptin-metformin sustained-release tablet according to claim 1, characterized in that: The extended-release tablet core contains the following ingredients based on 1000 servings: 500-1000g metformin hydrochloride, 50-100g resistant starch, 50-90g microcrystalline cellulose, 1-5g sodium bicarbonate, 1-5g magnesium stearate, 5-10g polyvinylpyrrolidone, 1-3g micropowdered silica and 0.5-2g silicon dioxide.

5. The small-sized sitagliptin-metformin sustained-release tablet according to claim 4, characterized in that: Enteric coating contains the following ingredients: 4-6g acrylic resin No. II, 1-3g hydroxypropyl methylcellulose phthalate, 2g hydroxypropyl methylcellulose, 1g polyethylene glycol 4000.

6. The small-sized sitagliptin-metformin sustained-release tablet according to claim 4, characterized in that: The immediate-release layer includes the following ingredients: 45-50 g sitagliptin, 6-10 g hydroxypropyl methylcellulose, 0.2-0.5 g talc, and 0.2-0.5 g silicon dioxide.

7. The small-sized sitagliptin-metformin sustained-release tablet according to claim 4, characterized in that: The ingredients of the sustained-release tablet core include: 500g of metformin hydrochloride, 80g of resistant starch, 50g of microcrystalline cellulose, 1g of sodium bicarbonate, 8g of polyvinylpyrrolidone, 1g of micropowdered silica, and 0.5g of silicon dioxide; The enteric coating comprises the following ingredients: acrylic resin No. II 4 g, hydroxypropyl methylcellulose phthalate 1 g, hydroxypropyl methylcellulose 2 g, and polyethylene glycol 4000 1 g; The immediate-release layer includes the following ingredients: sitagliptin 45 g, hydroxypropyl methylcellulose 8 g, talc 0.5 g, and silicon dioxide 0.2 g.

8. The small-sized sitagliptin-metformin sustained-release tablet according to claim 4, characterized in that: The ingredients of the sustained-release tablet core include: 1000g of metformin hydrochloride, 50g of resistant starch, 60g of microcrystalline cellulose, 3g of sodium bicarbonate, 10g of polyvinylpyrrolidone, 3g of micropowdered silica, 1g of silicon dioxide, and 5g of magnesium stearate; Enteric coating includes the following ingredients: acrylic resin No. II 6g, hydroxypropyl methylcellulose phthalate 3g, hydroxypropyl methylcellulose 2g and polyethylene glycol 4000 1g; The immediate-release layer includes the following ingredients: sitagliptin 50 g, hydroxypropyl methylcellulose 6 g, talc 0.3 g, and silicon dioxide 0.5 g.

9. The small-sized sitagliptin-metformin sustained-release tablet according to claim 4, characterized in that: The ingredients of the sustained-release tablet core include: 800g of metformin hydrochloride, 100g of resistant starch, 90g of microcrystalline cellulose, 5g of sodium bicarbonate, 6g of polyvinylpyrrolidone, 1g of micropowdered silica, 2g of silicon dioxide, and 1g of magnesium stearate; The enteric coating comprises the following ingredients: acrylic resin No. II 5 g, hydroxypropyl methylcellulose phthalate 2 g, hydroxypropyl methylcellulose 2 g, polyethylene glycol 4000 1 g; The immediate-release layer includes the following ingredients: sitagliptin 48 g, hydroxypropyl methylcellulose 8 g, talc 0.4 g, and silicon dioxide 0.3 g.

10. A method for preparing the small-sized sitagliptin-metformin sustained-release tablets according to any one of claims 1 to 9, characterized in that: The following steps are involved: After mixing the components of the sustained-release tablet core, granulating the mixture using a dry granulator to obtain the sustained-release tablet core; Dissolving the enteric coating components in 75-95% ethanol solution to obtain a first coating solution; Using a coating machine, coating the first coating liquid on the outside of the sustained-release tablet core to obtain a first crude product; Add water to the ingredients of the immediate-release layer and stir thoroughly to obtain a second coating solution; Using a coating machine, coating the outside of the first crude product with the second coating liquid to obtain a second crude product; adding water to the gastric soluble coating ingredients and stirring to obtain a third coating solution; The third coating liquid is coated on the outside of the second crude product by a coating machine to obtain small sitagliptin-metformin sustained-release tablets.

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