Sitagliptin metformin sustained release tablet and preparation process thereof

Abstract

The invention discloses a sitagliptin and metformin sustained release tablet and a preparation process thereof, and belongs to the technical field of medicines. The sitagliptin and metformin sustained release tablet is prepared from the following components in percentage by weight: 30 to 35 percent of coated sitagliptin microcapsules, 58 to 62 percent of metformin particles, 5 to 10 percent of an outer layer disintegrating agent and 0.5 to 1 percent of a lubricating agent. The preparation method comprises the following steps: firstly, mixing the coated sitagliptin microcapsules, metformin particles, an outer layer disintegrating agent and a lubricating agent, and then tabletting to obtain the sitagliptin metformin sustained release tablet. The sitagliptin metformin sustained-release tablet provided by the invention has excellent moisture resistance and stability, and the quality and curative effect of the medicine can be ensured.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and in particular relates to a sitagliptin metformin sustained-release tablet and a preparation process thereof. Background Art

[0002] The combination preparation of sitagliptin and metformin is the core drug for the treatment of type 2 diabetes. Sitagliptin inhibits the activity of DPP-4 enzyme, increases the levels of endogenous glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, promotes insulin secretion in a glucose-dependent manner, reduces glucagon secretion, and thus lowers postprandial blood glucose; metformin mainly activates the AMPK pathway, inhibits hepatic gluconeogenesis, reduces intestinal absorption of glucose, and improves peripheral tissue sensitivity to insulin, thereby lowering fasting blood glucose.

[0003] Currently, mainstream extended-release tablets (such as Janumet XR) utilize a dual-layer structure consisting of an immediate-release layer and a sustained-release layer, balancing the need for rapid onset of action with long-term efficacy. However, the organic solvent coating process for existing extended-release tablets still has certain drawbacks. Suspension spraying leads to uneven distribution of sitagliptin; talc introduces metal impurities that catalyze the formation of nitrosamines; the high water vapor permeability of the hydrophilic polymer coating layer causes hygroscopic degradation of metformin and tablet cracking; and migration between the two API layers in hot and humid environments triggers solid-state proton transfer reactions, accelerating the formation of highly toxic impurities NTTP and NDMA. Summary of the Invention

[0004] Based on the deficiencies of the prior art, the object of the present invention is to provide a sitagliptin metformin sustained-release tablet and a preparation process thereof.

[0005] The first aspect of the present invention is to provide a sitagliptin metformin sustained-release tablet, which comprises the following components by weight percentage: 30-35% of coated sitagliptin microcapsules, 58-62% of metformin granules, 5-10% of an outer layer disintegrant, and 0.5-1% of a lubricant; Wherein, the coated sitagliptin microcapsules are prepared by the following steps: (1) heating and melting the solid lipid material to obtain molten lipid; (2) continuously adding micronized sitagliptin to the molten lipids and dispersing the mixture under inert gas to form a suspension; (3) adding an antioxidant and a glidant to the suspension and mixing them uniformly to obtain a sitagliptin-lipid solution; (4) The sitagliptin-lipid solution is sprayed onto the inert carrier particles in an atomized form, and after solidification, the sitagliptin-coated microcapsules are obtained.

[0006] In some embodiments, the outer layer disintegrant is selected from at least one of sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone; and the lubricant is sodium stearyl fumarate.

[0007] In some embodiments, the solid lipid material is glyceryl behenate; and the mass ratio of the solid lipid material to the micronized sitagliptin is 1:2.5-3.2.

[0008] It should be noted that behenic acid glyceryl is a fatty acid glyceride formed by behenic acid and glycerol. In its molecular structure, the long-chain alkyl part of behenic acid has strong hydrophobicity. Its β' crystal form can make the molecules arranged more tightly and orderly, thereby enhancing its hydrophobic effect and forming a dense hydrophobic layer. The tortuosity of the water molecule penetration path is much higher than that of other lipids, which can effectively block the invasion of water molecules.

[0009] In some embodiments, the antioxidant is selected from at least one of BHT, TBHQ, and sodium L-ascorbate; and the amount of the antioxidant is 18-22% of the amount of micronized sitagliptin.

[0010] In some embodiments, the glidant is colloidal silicon dioxide; the amount of the glidant is 14-17% of the amount of micronized sitagliptin.

[0011] It should be noted that antioxidants can block the lipid oxidation chain reaction, and glidants can improve the atomization performance of the drug solution.

[0012] In some embodiments, the micronized sitagliptin has a D90 of ≤ 20 μm; the inert carrier particles are microcrystalline cellulose spheres or mannitol particles; the particle size of the inert carrier particles is 180-250 μm; and the amount of the sitagliptin-lipid solution is 20-30% of the weight of the inert carrier particles.

[0013] It should be noted that if the particle size of the inert carrier is too small, it is easy to stick together and cause agglomeration, and if the particle size is too large, it is easy to cause uneven coating.

[0014] In some embodiments, the heating temperature in step (1) is 70-80° C.; the stirring speed in step (2) is 500-1000 rpm, and the stirring time is 10-12 min.

[0015] In some embodiments, the mixing time in step (3) is 10-15 min; the atomization pressure in step (4) is 1.5-3 bar, and the curing temperature is 2-5°C.

[0016] It should be noted that the present invention sets the curing temperature to 2-5°C. The low-temperature curing coating is to prevent thermal degradation of sitagliptin and damage to the drug stability, while physically maintaining the colloidal structure of the lipid and inhibiting its oxidation and hydrolysis.

[0017] The second aspect of the present invention is to provide a preparation process of sitagliptin metformin sustained-release tablets, comprising the following steps: S1: Mixing the coated sitagliptin microcapsules, metformin granules, outer layer disintegrant and lubricant; S2: Tableting the mixed system obtained in S1 to obtain sitagliptin and metformin sustained-release tablets.

[0018] In some embodiments, in S1, the mixing time is 5-10 min, and the mixing speed is 15-20 rpm; in S2, the tableting die size is 8-12 mm, and the tableting compression force is 8-15 kN.

[0019] Compared with the prior art, the present invention has the following beneficial effects: The present invention creatively utilizes molten lipids to encapsulate sitagliptin, effectively isolating sitagliptin from the surrounding environment, significantly reducing water absorption and interaction with metformin and its potential degradation products, lowering the risk of chemical reactions, and significantly improving the long-term stability of sitagliptin. It also helps inhibit the formation of nitrosamine impurities. The lipid-coated microparticles have an excellent regular morphology and good fluidity, allowing them to be evenly distributed in the tablets, ensuring uniform content of the two drugs in each tablet and consistency in drug quality and efficacy.

[0020] The present invention adds micronized sitagliptin when preparing the coated sitagliptin microcapsules. The micronized sitagliptin drug can improve the dispersibility, so that it is more evenly loaded on the surface of the inert carrier particles during subsequent atomization spraying. The low-temperature atomization coating can form a continuous and uniform lipid film on the carrier surface, and the inert carrier particles can provide mechanical strength, thereby avoiding the adhesion and agglomeration of the lipid particles.

[0021] The lipid membrane provided by the present invention can also rupture rapidly after disintegration (dissolve within 1 minute after contact with the dissolution medium), achieving a synchronized release rate of sitagliptin and metformin. At the same time, the lipid layer delays drug release by less than 30 seconds, preventing local high-concentration stimulation from leading to excessive blood drug concentration and increasing the risk of adverse reactions, making the drug concentration in the body more stable, better controlling blood sugar levels, and optimizing the hypoglycemic effect. DETAILED DESCRIPTION

[0022] The present invention will be further described in detail below with reference to the embodiments.

[0023] Example 1 A sitagliptin metformin sustained-release tablet, comprising the following components by weight: 33% coated sitagliptin microcapsules, 60% metformin granules, 6% outer layer disintegrant, and 1% lubricant; Wherein, the coated sitagliptin microcapsules are prepared by the following steps: (1) Glyceryl behenate is heated and melted at 75°C to obtain molten lipid.

[0024] (2) Micronized sitagliptin (D90 ≤ 20 μm) was continuously added to the molten lipid, an inert gas was introduced, and the mixture was stirred and dispersed at 800 rpm for 12 min to form a suspension; the mass ratio of the solid lipid material to the micronized sitagliptin was 1:3.

[0025] (3) BHT and colloidal silicon dioxide were added to the suspension and mixed for 12 min to obtain a sitagliptin-lipid solution; wherein the amount of antioxidant was 20% of the amount of micronized sitagliptin; and the amount of glidant was 15% of the amount of micronized sitagliptin.

[0026] (4) The sitagliptin-lipid solution was sprayed in an atomized form on microcrystalline cellulose spheres with a particle size of 200 μm at a pressure of 2 bar, and solidified at 3°C ​​to obtain sitagliptin-coated microcapsules; wherein the amount of sitagliptin-lipid solution used was 25% of the weight of the inert carrier particles.

[0027] The above-mentioned sitagliptin metformin sustained-release tablets are prepared by the following steps: S1: Mix the coated sitagliptin microcapsules, metformin granules, sodium carboxymethyl starch and sodium stearyl fumarate at 20 rpm for 10 min.

[0028] S2: The mixed system obtained in S1 was tableted; the tableting die size was 10 mm and the tableting compression force was 12 kN.

[0029] Example 2 It is basically the same as Example 1, with the only difference being: Sitagliptin metformin sustained-release tablets include the following components by weight percentage: 35% coated sitagliptin microcapsules, 58% metformin granules, 6% outer layer disintegrant, and 1% lubricant.

[0030] Example 3 It is basically the same as Example 1, except that: Sitagliptin metformin sustained-release tablets include the following components by weight percentage: 30% coated sitagliptin microcapsules, 62% metformin granules, 7.5% outer layer disintegrant, and 0.5% lubricant.

[0031] Example 4 It is basically the same as Example 1, with the only difference being: Sitagliptin-coated microcapsules are prepared by the following steps: (1) Glyceryl behenate is heated and melted at 75°C to obtain molten lipid.

[0032] (2) Micronized sitagliptin (D90 ≤ 20 μm) was continuously added to the molten lipid, an inert gas was introduced, and the mixture was stirred and dispersed at 500 rpm for 10 min to form a suspension; the mass ratio of the solid lipid material to the micronized sitagliptin was 1:2.5.

[0033] (3) TBHQ and colloidal silicon dioxide were added to the suspension and mixed for 10 min to obtain a sitagliptin-lipid solution; wherein the amount of antioxidant was 18% of the amount of micronized sitagliptin; the amount of glidant was 14% of the amount of micronized sitagliptin.

[0034] (4) The sitagliptin-lipid solution was sprayed in an atomized form on mannitol particles with a particle size of 180 μm at a pressure of 1.5 bar, and solidified at 2°C to obtain sitagliptin-coated microcapsules; wherein the amount of sitagliptin-lipid solution used was 30% of the weight of the inert carrier particles.

[0035] Example 5 It is basically the same as Example 1, with the only difference being: Sitagliptin-coated microcapsules are prepared by the following steps: (1) Glyceryl behenate is heated and melted at 80°C to obtain molten lipid.

[0036] (2) Micronized sitagliptin (D90 ≤ 20 μm) was continuously added to the molten lipid, an inert gas was introduced, and the mixture was stirred and dispersed at 1000 rpm for 12 min to form a suspension; the mass ratio of the solid lipid material to the micronized sitagliptin was 1:3.2.

[0037] (3) Sodium L-ascorbate and colloidal silicon dioxide were added to the suspension and mixed for 15 min to obtain a sitagliptin-lipid solution; wherein the amount of antioxidant was 22% of the amount of micronized sitagliptin; and the amount of glidant was 17% of the amount of micronized sitagliptin.

[0038] (4) The sitagliptin-lipid solution was sprayed in an atomized form on microcrystalline cellulose spheres with a particle size of 250 μm at a pressure of 3 bar, and solidified at 5°C to obtain sitagliptin-coated microcapsules; wherein the amount of sitagliptin-lipid solution used was 20% of the weight of the inert carrier particles.

[0039] Comparative Example 1 On the basis of Example 1, the step of coating sitagliptin microcapsules was omitted, that is, the same amount of sitagliptin granules were directly added into the preparation process of sitagliptin metformin sustained-release tablets for tableting.

[0040] Comparative Example 2 On the basis of Example 1, high temperature curing coating was adopted in the step of coating sitagliptin microcapsules, that is, in the step (4) of coating sitagliptin microcapsules, the curing temperature was 20°C.

[0041] Comparative Example 3 On the basis of Example 1, glyceryl behenate was replaced with silicon dioxide nano-coating.

[0042] Test Example 1 Moisture resistance test: The sitagliptin metformin sustained-release tablets prepared in Examples 1-5 and Comparative Examples 1-3 were weighed to obtain W1, then placed in a high-humidity environment at 25°C and 93% relative humidity (RH) for 7 days. The tablets were then weighed again to obtain W2, and the weight gain was calculated. The test results are shown in Table 1.

[0043] Table 1 As can be seen from Table 1, the sitagliptin metformin sustained-release tablets prepared in the examples had a small weight gain before and after, and had good moisture resistance, while the weight gain rates of the comparative examples were all high. Among them, Comparative Example 1 did not use lipid to encapsulate sitagliptin, resulting in a significant decrease in moisture resistance and a significant weight gain before and after moisture absorption. Comparative Example 3 replaced the lipid coating (glyceryl behenate) with an inorganic isolation layer (silicon dioxide nanocoating). Due to pinhole defects in the nano-scale coating, water vapor easily permeated, resulting in a decrease in moisture resistance.

[0044] Test Example 2 Stability test: The sitagliptin metformin sustained-release tablets prepared in Examples 1-5 and Comparative Examples 1-3 were placed in an incubator at a relative humidity (RH) of 65% ± 5% and a temperature of 30°C ± 2°C for 6 consecutive months. The total impurities (%) were measured at 0 and 6 months, respectively. The experimental results are shown in Table 2.

[0045] Table 2 As can be seen from Table 2, the sitagliptin metformin sustained-release tablets provided in the embodiment of the present invention have excellent stability, and the impurity content changes little in the stability test. Comparative Example 1 omits the sitagliptin microcapsule coating step and does not adopt physical isolation, resulting in decreased stability and a significant increase in impurity content.

[0046] Test Example 3 Dissolution test: The sitagliptin and metformin sustained-release tablets obtained in Examples 1-5 and Comparative Examples 1-3 were tested. According to the dissolution test method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Rules 0931, Method 2, Paddle Method), pH 6.8 phosphate buffer was used as the dissolution medium, the temperature was 37±0.5°C, and the rotation speed was 50-100 rpm. The cumulative release rate (%) of sitagliptin phosphate was measured at 10 min, 15 min, 20 min, 30 min, and 45 min, and the cumulative release rate (%) of metformin hydrochloride was measured at 0.5 h, 2 h, 4 h, 8 h, and 12 h. Cumulative release rate = drug release amount at sampling point / total drug amount of the preparation × 100%. The test results are shown in Tables 3 and 4.

[0047] Table 3 Table 4 Sustained-release tablets of sitagliptin should disintegrate or dissolve rapidly in the gastrointestinal tract to rapidly exert their DPP-4 inhibitory effects, promote insulin secretion, and lower blood sugar, ensuring rapid absorption and stable blood concentrations. Metformin, on the other hand, should be released slowly and evenly in the gastrointestinal tract to maintain effective blood concentrations over a long period of time. A combination of Tables 3 and 4 demonstrates that the sitagliptin-coated microcapsules prepared in the present invention are capable of coordinated release with metformin. Comparative Example 3, however, exhibits an excessively rapid release rate due to the poor moisture resistance of the inorganic barrier layer used.

[0048] The above are only some embodiments of the present invention. For those skilled in the art, several modifications and improvements can be made without departing from the inventive concept of the present invention, which all fall within the scope of protection of the present invention.

Claims

1. A sitagliptin metformin sustained-release tablet, characterized in that: The composition comprises the following components by weight percentage: 30-35% of coated sitagliptin microcapsules, 58-62% of metformin granules, 5-10% of outer layer disintegrant, and 0.5-1% of lubricant; Wherein, the coated sitagliptin microcapsules are prepared by the following steps: heating and melting the solid lipid material to obtain molten lipid; continuously adding micronized sitagliptin to the molten lipid and dispersing the mixture under inert gas to form a suspension; adding an antioxidant and a glidant to the suspension, and mixing them uniformly to obtain a sitagliptin-lipid solution; The sitagliptin-lipid drug solution is sprayed on the inert carrier particles in an atomized form, and the sitagliptin-coated microcapsules are obtained after solidification.

2. The sitagliptin metformin sustained-release tablet according to claim 1, wherein The outer layer disintegrant is selected from at least one of sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone; and the lubricant is sodium stearyl fumarate.

3. The sitagliptin metformin sustained-release tablet according to claim 1, characterized in that The solid lipid material is glyceryl behenate; the mass ratio of the solid lipid material to the micronized sitagliptin is 1:2.5-3.

2.

4. The sitagliptin metformin sustained-release tablet according to claim 1, characterized in that The antioxidant is selected from at least one of BHT, TBHQ, and L-sodium ascorbate; the amount of the antioxidant is 18-22% of the amount of the micronized sitagliptin.

5. The sitagliptin metformin sustained-release tablet according to claim 1, characterized in that The glidant is colloidal silicon dioxide; the amount of the glidant is 14-17% of the amount of the micronized sitagliptin.

6. The sitagliptin metformin sustained-release tablet according to claim 1, characterized in that The micronized sitagliptin has a D90 of ≤ 20 μm; the inert carrier particles are microcrystalline cellulose spheres or mannitol particles; the particle size of the inert carrier particles is 180-250 μm; and the amount of the sitagliptin-lipid solution is 20-30% of the weight of the inert carrier particles.

7. The sitagliptin metformin sustained-release tablet according to claim 1, characterized in that In the step (1), the heating temperature is 70-80° C.; in the step (2), the stirring speed is 500-1000 rpm, and the stirring time is 10-12 min.

8. The sitagliptin metformin sustained-release tablet according to claim 1, characterized in that In the step (3), the mixing time is 10-15 min; in the step (4), the atomization pressure is 1.5-3 bar, and the curing temperature is 2-5°C.

9. A process for preparing the sitagliptin metformin sustained-release tablets according to any one of claims 1 to 8, characterized in that: The following steps are involved: S1: mixing the coated sitagliptin microcapsules, the metformin granules, the outer layer disintegrant and the lubricant; S2: Tableting the mixed system obtained in S1 to obtain the sitagliptin metformin sustained-release tablets.

10. The preparation process according to claim 9, characterized in that: In the S1, the mixing time is 5-10 min, and the mixing speed is 15-20 rpm; in the S2, the tableting die size is 8-12 mm, and the tableting compression force is 8-15 kN.

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