A sitagliptin metformin sustained-release tablet and a preparation process thereof

Abstract

The application discloses a sitagliptin and metformin sustained-release tablet and a preparation process thereof, and belongs to the technical field of medicines.A sitagliptin and metformin sustained-release tablet comprises the following components in percentage by weight: 30-35% of coated sitagliptin microcapsules, 58-62% of metformin granules, 5-10% of outer layer disintegrating agents and 0.5-1% of lubricants.The coated sitagliptin microcapsules, the metformin granules, the outer layer disintegrating agents and the lubricants are mixed first, and then tableting is carried out, so that the sitagliptin and metformin sustained-release tablet is obtained.The sitagliptin and metformin sustained-release tablet provided by the application has excellent moisture resistance and stability, and can guarantee the quality and curative effect of medicines.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicines, and particularly relates to a sitagliptin metformin sustained-release tablet and a preparation process thereof. BACKGROUND

[0002] The compound preparation of sitagliptin and metformin is a core drug for treating type 2 diabetes, sitagliptin increases the levels of endogenous glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide by inhibiting DPP-4 enzyme activity, 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 the absorption of glucose in the intestinal tract, and improves the sensitivity of peripheral tissues to insulin, thereby lowering fasting blood glucose.

[0003] At present, mainstream sustained-release tablets (such as Janumet XR) are designed by a double-layer structure of a quick-release layer + a sustained-release layer to balance the requirements of onset speed and long-acting maintenance. However, the organic solvent coating process of the existing sustained-release tablet technology still has certain defects, the suspension liquid spraying drug causes uneven distribution of sitagliptin, the introduction of talc powder causes the catalysis of metal impurities to generate nitrosamine, the water vapor transmission rate of the hydrophilic polymer material coating layer is too high to cause the hygroscopic degradation of metformin and the cracking of the tablet, the interlayer migration of the double API under a humid heat environment triggers a solid-state proton transfer reaction, and accelerates the generation of toxic impurities NTTP and NDMA. SUMMARY

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

[0005] The first aspect of the present application is to provide a sitagliptin metformin sustained-release tablet, which comprises the following components in percentage by weight: 30-35% of coated sitagliptin microcapsules, 58-62% of metformin granules, 5-10% of outer layer disintegrants, and 0.5-1% of lubricants.

[0006] The coated sitagliptin microcapsules are prepared by the following steps:

[0007] (1) melt a solid lipid material to obtain a molten lipid;

[0008] (2) continuously add micronized sitagliptin into the molten lipid to form a suspension under the protection of inert gas;

[0009] (3) add an antioxidant and a glidant into the suspension to obtain a sitagliptin-lipid liquid medicine by mixing uniformly;

[0010] (4) spray the sitagliptin-lipid liquid medicine in the form of atomization on inert carrier particles, and obtain the coated sitagliptin microcapsules after solidification.

[0011] In some embodiments, the outer layer disintegrant is selected from at least one of sodium carboxymethyl starch, cross-linked polyplasdone; and the lubricant is sodium stearyl fumarate.

[0012] 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.

[0013] It should be noted that glyceryl behenate is a fatty acid glyceride formed by behenic acid and glycerol, and in the molecular structure, the long-chain alkyl part of behenic acid has strong hydrophobicity, and the β' crystal form can make the molecular arrangement more compact and orderly, so that the hydrophobic effect is enhanced, thereby forming a dense hydrophobic layer, and 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.

[0014] 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 the micronized sitagliptin.

[0015] In some embodiments, the glidant is colloidal silicon dioxide; and the amount of the glidant is 14-17% of the amount of the micronized sitagliptin.

[0016] It should be noted that the antioxidant can block the lipid oxidation chain reaction, and the glidant can improve the atomization performance of the drug solution.

[0017] In some embodiments, the D90 of the micronized sitagliptin is ≤ 20 μm; the inert carrier particles are microcrystalline cellulose pellets or mannitol particles; the particle size of the inert carrier particles is 180-250 μm; and the amount of the sitagliptin-lipid drug solution is 20-30% of the weight of the inert carrier particles.

[0018] It should be noted that if the particle size of the inert carrier particles is too small, it is easy to cause agglomeration due to adhesion, and if the particle size is too large, it is easy to cause uneven coating.

[0019] In some embodiments, the heating temperature in step (1) is 70-80℃; the stirring speed in step (2) is 500-1000 rpm, and the stirring time is 10-12 min.

[0020] 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 solidification temperature is 2-5℃.

[0021] It should be noted that the solidification temperature is set to 2-5℃ in the present application, and the low-temperature solidification coating is to prevent the thermal degradation of sitagliptin and damage the stability of the drug, while physically maintaining the gel crystal structure of the lipid and inhibiting its oxidation and hydrolysis.

[0022] The second aspect of the present application is to provide a preparation process of sitagliptin metformin sustained-release tablets, comprising the following steps:

[0023] S1: mixing the coated sitagliptin microcapsules, metformin particles, outer layer disintegrant and lubricant;

[0024] S2: tabletting the mixed system obtained in S1 to obtain the sitagliptin metformin sustained-release tablets.

[0025] In some embodiments, in S1, the mixing time is 5-10 min and the mixing rotation speed is 15-20 rpm; in S2, the tabletting punch size is 8-12 mm and the tabletting compression force is 8-15 kN.

[0026] Compared with the prior art, the present application has the following beneficial effects:

[0027] The present application creatively utilizes the molten lipid to wrap sitagliptin, effectively isolates the contact between sitagliptin and the surrounding environment, significantly reduces the moisture absorption and the interaction with metformin and its potential degradation products, reduces the risk of chemical reaction, greatly improves the long-term stability of sitagliptin, and helps to inhibit the formation of impurities nitrosamine; the lipid-coated microparticles have excellent regular morphology and good flowability, can be uniformly distributed in the tablets, ensure the uniformity of the content of the two drugs in each tablet, and ensure the consistency of the quality and efficacy of the drug.

[0028] In the preparation of the coated sitagliptin microcapsules, micronized sitagliptin is added, which can improve the dispersibility and make it more uniformly 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 surface of the carrier, and the inert carrier particles can provide mechanical strength, avoiding the adhesion and agglomeration of lipid particles.

[0029] The lipid film provided by the present application can also rapidly break down after disintegration (dissolve within 1 minute after contacting the dissolution medium), realizing the synchronous release rate of sitagliptin and metformin. At the same time, the lipid layer delays drug release for less than 30 seconds, preventing local high concentration stimulation from causing excessively high blood drug concentration, increasing the risk of adverse reactions, making the drug concentration in the body more stable, better controlling the blood glucose level, and optimizing the hypoglycemic effect. DETAILED DESCRIPTION

[0030] The present application will be further described in detail below in combination with examples.

[0031] Example 1

[0032] A sitagliptin metformin sustained release tablet comprises the following components by weight percentage: 33% of coated sitagliptin microcapsules, 60% of metformin granules, 6% of outer layer disintegrant, and 1% of lubricant.

[0033] The coated sitagliptin microcapsules are prepared by the following steps:

[0034] (1) Glyceryl behenate is heated and melted at 75°C to obtain a molten lipid.

[0035] (2) Micronized sitagliptin (D90 ≤ 20 μm) is continuously added to the molten lipid, inert gas is introduced, and stirring and dispersion are performed at a speed of 800 rpm for 12 min to form a suspension; the mass ratio of solid lipid material to micronized sitagliptin is 1:3.

[0036] (3) BHT and colloidal silicon dioxide are added to the suspension, and mixing is performed for 12 min to obtain a sitagliptin-lipid solution; the amount of antioxidant is 20% of the amount of micronized sitagliptin; the amount of flow aid is 15% of the amount of micronized sitagliptin.

[0037] (4) The sitagliptin-lipid solution is sprayed in an atomized form on microcrystalline cellulose spherical particles with a particle size of 200 μm under a pressure of 2 bar, and is solidified at 3°C to obtain coated sitagliptin microcapsules; the amount of sitagliptin-lipid solution is 25% of the weight of the inert carrier particles.

[0038] The above-mentioned sitagliptin metformin sustained release tablet is prepared by the following steps:

[0039] S1: The coated sitagliptin microcapsules, metformin granules, sodium carboxymethyl starch, and sodium stearyl fumarate are mixed at a speed of 20 rpm for 10 min.

[0040] S2: The mixed system obtained in S1 is subjected to tabletting; the tabletting die size is 10 mm, and the tabletting compression force is 12 kN.

[0041] Example 2

[0042] The example is basically the same as example 1, and the only difference is that:

[0043] The sitagliptin metformin sustained release tablet comprises the following components by weight percentage: 35% of coated sitagliptin microcapsules, 58% of metformin granules, 6% of outer layer disintegrant, and 1% of lubricant.

[0044] Example 3

[0045] The example is basically the same as example 1, and the only difference is that:

[0046] The Sitagliptin Metformin Hydrochloride Extended Release Tablets comprise the following components by weight percentage: Sitagliptin microcapsule coated 30%, Metformin hydrochloride granules 62%, outer layer disintegrant 7.5%, lubricant 0.5%.

[0047] Example 4

[0048] The example 1 is basically consistent, the difference is only in that:

[0049] The Sitagliptin microcapsule coated is prepared by the following steps:

[0050] (1) The glyceryl behenate is heated to melt at 75°C to obtain a molten lipid.

[0051] (2) The micronized Sitagliptin (D90 ≤ 20 μm) is continuously added into the molten lipid, and an inert gas is introduced to stir and disperse for 10 min at a speed of 500 rpm to form a suspension; the mass ratio of the solid lipid material to the micronized Sitagliptin is 1:2.5.

[0052] (3) The TBHQ and colloidal silicon dioxide are added into the suspension, and mixed for 10 min to obtain a Sitagliptin-lipid drug solution; wherein, the dosage of the antioxidant is 18% of the dosage of the micronized Sitagliptin; the dosage of the glidant is 14% of the dosage of the micronized Sitagliptin.

[0053] (4) The Sitagliptin-lipid drug solution is sprayed in the form of atomization on the mannitol particles with a particle size of 180 μm under a pressure of 1.5 bar, and is solidified at 2°C to obtain the Sitagliptin microcapsule coated; wherein, the dosage of the Sitagliptin-lipid drug solution is 30% of the weight of the inert carrier particles.

[0054] Example 5

[0055] The example 1 is basically consistent, the difference is only in that:

[0056] The Sitagliptin microcapsule coated is prepared by the following steps:

[0057] (1) The glyceryl behenate is heated to melt at 80°C to obtain a molten lipid.

[0058] (2) The micronized Sitagliptin (D90 ≤ 20 μm) is continuously added into the molten lipid, and an inert gas is introduced to stir and disperse for 12 min at a speed of 1000 rpm to form a suspension; the mass ratio of the solid lipid material to the micronized Sitagliptin is 1:3.2.

[0059] (3) The sodium L-ascorbate and colloidal silicon dioxide are added into the suspension, and mixed for 15 min to obtain a Sitagliptin-lipid drug solution; wherein, the dosage of the antioxidant is 22% of the dosage of the micronized Sitagliptin; the dosage of the glidant is 17% of the dosage of the micronized Sitagliptin.

[0060] (4) Spraying the Sitagliptin-lipid solution on the microcrystalline cellulose particles with a particle size of 250 μm under a pressure of 3 bar in the form of atomization, and solidifying at 5°C to obtain Sitagliptin microcapsules coated.

[0061] Comparative Example 1

[0062] Based on Example 1, the step of coating Sitagliptin microcapsules was omitted, i.e. the same amount of Sitagliptin granules was directly added in the preparation process of Sitagliptin Metformin sustained-release tablets for tabletting.

[0063] Comparative Example 2

[0064] Based on Example 1, high-temperature solidification coating was used in the step of coating Sitagliptin microcapsules, i.e. in the step (4) of coating Sitagliptin microcapsules, the solidification temperature was 20°C.

[0065] Comparative Example 3

[0066] Based on Example 1, glyceryl behenate was replaced by silica nano-coating.

[0067] Test Example 1

[0068] Moisture resistance test:

[0069] The Sitagliptin Metformin sustained-release tablets prepared in Examples 1-5 and Comparative Examples 1-3 were weighed to obtain W1, and then placed in a high-humidity environment with a temperature of 25°C and a relative humidity (RH) of 93% for 7 days, and then weighed again to obtain W2, and the weight gain rate was calculated. The test results are shown in Table 1.

[0070] Table 1

[0071]

[0072] As can be seen from Table 1, the Sitagliptin Metformin sustained-release tablets prepared in the examples have a small weight gain range before and after, and have good moisture resistance, while the weight gain rates of the comparative examples are all high. Among them, Comparative Example 1 has a significant weight gain before and after moisture absorption due to the absence of lipid coating of Sitagliptin, resulting in a significant decrease in moisture resistance. In Comparative Example 3, the lipid coating (glyceryl behenate) was replaced by an inorganic barrier layer (silica nano-coating), and due to the pinhole defects of the nano-level coating, water vapor can easily penetrate, resulting in a decrease in moisture resistance.

[0073] Test Example 2

[0074] Stability test:

[0075] The siglitin and metformin sustained release tablets prepared in Examples 1-5 and Comparative Examples 1-3 were respectively placed in a 65%±5% relative humidity (RH) and 30℃±2℃ temperature incubator for continuous placement of 6 months, and the total impurity (%) was determined at 0 months and 6 months, respectively. The experimental results are shown in Table 2.

[0076] Table 2

[0077]

[0078] As can be seen from Table 2, the siglitin and metformin sustained release tablets provided by the embodiments of the present application have excellent stability, and the impurity content changes little in the stability test. Comparative Example 1 omits the step of coating the siglitin microcapsules, and does not use physical isolation, resulting in a decrease in stability and a significant increase in impurity content.

[0079] Test Example 3

[0080] Dissolution test:

[0081] The siglitin 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 0931 Method 2), pH 6.8 phosphate buffer was used as the dissolution medium, the temperature was 37±0.5℃, the rotation speed was 50-100 rpm, and the cumulative release rate (%) of phosphonic acid siglitin was determined at 10 min, 15 min, 20 min, 30 min and 45 min, and the cumulative release rate (%) of metformin hydrochloride was determined at 0.5 h, 2 h, 4 h, 8 h, 12 h, and the cumulative release rate = sample point drug release amount / total drug amount of the preparation x 100%. The test results are shown in Tables 3 and 4.

[0082] Table 3

[0083]

[0084] Table 4

[0085]

[0086] The siglitin sustained release tablets should be rapidly disintegrated or dissolved in the gastrointestinal tract to rapidly exert its effect of inhibiting DPP-4 enzyme, promoting insulin secretion, and reducing blood sugar, so as to ensure rapid absorption of the drug in the body and stable blood drug concentration; and the metformin should be slowly and uniformly released in the gastrointestinal tract to maintain effective blood drug concentration for a long time. As can be seen from Tables 3 and 4, the coated siglitin microcapsules prepared in the present application can be released in combination with metformin, and Comparative Example 3 has poor moisture resistance due to the use of an inorganic isolation layer, resulting in too fast release rate.

[0087] The above merely describes some embodiments of the present application. For those skilled in the art, without departing from the concept of the present application, several modifications and improvements can be made, which are within the protection scope of the present application.

Claims

1. A sustained release tablet of sitagliptin metformin characterized in that, By weight percentage, including the following components: coated sitagliptin microcapsules 30-35%, metformin particles 58-62%, outer layer disintegrant 5-10%, lubricant 0.5-1%; Wherein, the coated sitagliptin microcapsules are prepared by the following steps: (1) heating and melting the solid lipid material to obtain a molten lipid; (2) continuously adding micronized sitagliptin to the molten lipid, and dispersing to form a suspension under the protection of inert gas; (3) adding an antioxidant and a glidant to the suspension and mixing uniformly to obtain a sitagliptin-lipid drug solution; (4) spraying the sitagliptin-lipid drug solution in the form of atomization on inert carrier particles under an atomization pressure of 1.5-3 bar, and solidifying at 2-5°C to obtain the coated sitagliptin microcapsules; 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.

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

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

4. The sitagliptin and metformin extended release tablet according to claim 1, wherein the tablet is characterized by, The glidant is colloidal silicon dioxide; the amount of the glidant is 14-17% of the amount of the micronized sitagliptin.

5. The sitagliptin and metformin extended release tablet according to claim 1, wherein The micronized sitagliptin D90 ≤ 20 μm; the inert carrier particles are microcrystalline cellulose pellets or mannitol particles; the particle size of the inert carrier particles is 180-250 μm; the amount of the sitagliptin-lipid drug solution is 20-30% of the weight of the inert carrier particles.

6. The sitagliptin and metformin extended release tablet according to claim 1, wherein 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.

7. The sitagliptin and metformin extended release tablet according to claim 1, wherein the tablet is characterized by, In the step (3), the mixing time is 10-15 min.

8. A process for the preparation of the sustained release tablet of sitagliptin metformin hydrochloride according to any one of claims 1 to 7, characterized in that, Including the following steps: S1: mixing the coated sitagliptin microcapsules, the metformin particles, the outer layer disintegrant, and the lubricant; S2: tabletting the mixture obtained in S1 to obtain the sitagliptin metformin sustained-release tablets.

9. The manufacturing process of claim 8, wherein, In S1, the mixing time is 5-10 min, and the mixing speed is 15-20 rpm; in S2, the tabletting die size is 8-12 mm, and the tabletting compression force is 8-15 kN.

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