Fixed-dose composition of sitagliptin and metformin and preparation method thereof

Abstract

The invention provides a sitagliptin and metformin fixed-dose composition and a preparation method thereof, and relates to the technical field of medicines, and the sitagliptin and metformin fixed-dose composition comprises the following components in percentage by weight: 1-10% of sitagliptin, 1-10% of metformin and the balance of water. 50%-85% of metformin hydrochloride; 2%-10% of an adhesive and polymer; 0.5%-3% of a lubricant; 10%-40% of a filling agent; and 5%-20% of a stabilizer. The fixed-dose composition of sitagliptin and metformin and the preparation method of the fixed-dose composition are high in bioavailability, low in hygroscopicity, good in stability and easy for industrial production.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and in particular to a fixed-dose composition of sitagliptin and metformin and its preparation method. Background Technology

[0002] Type 2 diabetes is a common chronic metabolic disease, and its treatment often requires the combined use of drugs with different mechanisms of action. Sitagliptin is a potent DPP-4 inhibitor that controls blood glucose by increasing the concentration of active glucagon-like peptide-1 (GLP-1) in the body. Metformin hydrochloride is a first-line drug for treating type 2 diabetes, primarily working by inhibiting hepatic glucose output and improving peripheral insulin sensitivity. Formulating these two drugs into fixed-dose combination formulations (such as 50mg / 500mg, 50mg / 850mg, etc.) can improve patient convenience and adherence.

[0003] However, developing sitagliptin-metformin combination formulations faces several major technical challenges: Metformin hydrochloride has an absolute bioavailability of only about 50%. Due to its high effective dose (above 500 mg), the formulations are relatively large and may cause swallowing discomfort for patients. Therefore, there is an urgent need to improve its bioavailability.

[0004] Stability issues of sitagliptin: Sitagliptin contains an aminourea structure in its molecule, which is prone to degradation under high temperature and high humidity conditions, producing impurities and affecting the safety and efficacy of the drug.

[0005] Existing compound formulation technologies (such as reference patent 200680047103.7) typically employ a process of co-granulating two active pharmaceutical ingredients. However, under this process, sitagliptin is in prolonged contact with hygroscopic metformin hydrochloride, resulting in unsatisfactory stability. Summary of the Invention

[0006] The purpose of this invention is to provide a fixed-dose composition of sitagliptin and metformin and its preparation method, which has high bioavailability, low hygroscopicity, good stability and is easy to industrialize.

[0007] To achieve the above objectives, the present invention provides a fixed-dose composition of sitagliptin and metformin, comprising the following components in weight percentage: sitagliptin: 1%-10%; metformin hydrochloride: 50%-85%; binder and polymer: 2%-10%; lubricant: 0.5%-3%; filler: 10%-40%; stabilizer: 5%-20%.

[0008] Preferably, the stabilizer is a water-insoluble inorganic calcium salt.

[0009] Preferably, the amount of stabilizer used is 10%-15% of the total weight of the formulation.

[0010] Preferably, the adhesive is polyvinylpyrrolidone.

[0011] Preferably, the polymer includes one or more of Eudragit L-100 and Eudragit EPO.

[0012] Preferably, the lubricant is sodium stearate fumarate.

[0013] Preferably, the filler includes mannitol.

[0014] A method for preparing a fixed-dose composition of sitagliptin and metformin includes the following steps: Metformin hydrochloride, adhesive, and polymer were dissolved in an ethanol-water solution to prepare a spray solution; Using a packing material as the fluidized bed substrate, the spray solution is atomized and sprayed into the fluidized bed substrate. After drying, amorphous metformin particles are obtained. Sitagliptin, fillers, stabilizers, and amorphous metformin granules were premixed. The premix is ​​mixed with the lubricant to obtain the final mixture, which is then compressed into tablets.

[0015] Preferably, the liquid preparation rate sprayed into the fluidized bed substrate in the atomized form is 0.3~0.6 kg / min; The drying time to obtain amorphous metformin granules after drying is approximately 0.5~1.5 hours, and the temperature is 50~65℃. Premix for 10-20 minutes, and total mix for 5-15 minutes; Tableting speed: 40-80 thousand tablets / hour; pressure: 12-25 kN; tablet hardness: 120-220 N.

[0016] Therefore, the present invention employs the above-mentioned fixed-dose composition of sitagliptin and metformin and its preparation method, and the technical effects are as follows: A process for preparing metformin amorphous particles was employed. Specifically, an ethanol-water solution of metformin hydrochloride, binder, and polymer was sprayed onto the filler for one-step granulation. A second portion of sitagliptin phosphate, in its raw powder form, was added during the final mixing process along with other fillers, stabilizers, and lubricants. This process increases the bioavailability of metformin hydrochloride from 50% to over 85%, while significantly reducing the contact area and time between sitagliptin and a large amount of hygroscopic metformin hydrochloride during wet granulation, thus minimizing the risk of sitagliptin degradation from the process source.

[0017] Introducing water-insoluble inorganic calcium salts, particularly dicalcium phosphate (DCP), into the formulation is beneficial. DCP not only serves as a filler but, more importantly, it is non-hygroscopic and can absorb some of the moisture in the formulation, providing a relatively dry microenvironment for the system. Simultaneously, its calcium ions may weakly interact with sitagliptin or impurities, playing a stabilizing role. Detailed Implementation

[0018] The technical solution of the present invention will be further described below through embodiments.

[0019] Unless otherwise defined, the technical or scientific terms used in this invention shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0020] The effects of adding dicalcium phosphate internally or externally in a fluidized bed are not entirely the same: when added externally, it can provide a drier microenvironment for the system, which has a better effect on the stability of the product; if it is added internally as a substrate, it needs to be granulated with the aqueous solution. This process will introduce moisture, which will prevent it from providing a dry microenvironment and lose its stability-promoting function.

[0021] Eudragit L-100 and Eudragit EPO are from Evonik Operations GmbH; Calcium hydrogen phosphate is derived from Chemische Fabrik Budenheim KG; Mannitol is derived from Roquette Freres; Povidone is sourced from BASF Corporation.

[0022] Example 1 A method for preparing a fixed-dose composition of sitagliptin and metformin (50mg / 850mg, per 1000 tablets), wherein the composition formulation is as follows: sitagliptin phosphate: 64.25g, metformin hydrochloride: 850.0g, povidone: 18.0g, Eudragit L-100 (pH-responsive polyacrylic resin): 18.0g, Eudragit EPO (gastric-soluble acrylic resin): 15.0g, mannitol: 180.0g, microcrystalline cellulose: 50.75g, dicalcium phosphate: 20.0g, sodium stearate fumarate: 18.0g.

[0023] A method for preparing a fixed-dose composition of sitagliptin and metformin includes the following steps: Mannitol (passed through a 40-mesh sieve) was added to the fluidized bed as a substrate; Prepare an ethanol-water solution of metformin hydrochloride, povidone, Eudragit L-100 and Eudragit EPO as a spray solution; The spray solution is injected into the fluidized bed via top spraying, and the material temperature is controlled at approximately 35-45℃. After spraying, the material is dried at 55℃ to obtain amorphous metformin granules. The moisture content of the amorphous metformin granules is no higher than 2.0%. Amorphous metformin granules ; Mix the granulated amorphous metformin granules with added sitagliptin phosphate, microcrystalline cellulose, and dicalcium phosphate for 15 minutes. Add sodium stearate to a mixer and mix for 10 minutes, then compress into tablets using a rotary tablet press.

[0024] Example 2 A method for preparing a fixed-dose composition of sitagliptin and metformin (50 mg / 1000 mg, per 1000 tablets) is provided, with the same preparation steps as in Example 1. The composition formulation is as follows: sitagliptin phosphate: 64.25 g, metformin hydrochloride: 1000.0 g, povidone: 32.0 g, Eudragit L-100: 18.0 g, Eudragit EPO: 15.0 g, mannitol: 210.5 g, microcrystalline cellulose: 59.75 g, dicalcium phosphate: 23.5 g, sodium stearate fumarate: 21.0 g.

[0025] Example 3 A method for preparing a fixed-dose composition of sitagliptin and metformin specifically includes the following steps: 64.25 g of sitagliptin phosphate, 50.75 g of microcrystalline cellulose, 20.0 g of dicalcium phosphate and 180.0 g of mannitol were added to the fluidized bed as substrates. 850.0 g of metformin hydrochloride, 18.0 g of povidone, 18.0 g of Eudragit L-100 and 15.0 g of Eudragit EPO were dissolved in an ethanol-water solution to obtain a spray solution; The above-mentioned spray solution is sprayed into the fluidized bed using a top spray method, and the material temperature is controlled at about 35-45℃. After the spraying is completed, it is dried at 55℃ to obtain amorphous metformin granules. The moisture content of the amorphous metformin granules is not higher than 2.0%. Amorphous metformin granules ; The granulated amorphous metformin granules were mixed with sodium stearate in a mixer for 10 minutes and then compressed into tablets using a rotary tablet press.

[0026] Comparative Example 1 Following conventional processes and the formulation ratio of the composition in Example 1, wet granulation is performed, specifically including the following steps: Sitagliptin phosphate, metformin hydrochloride, and mannitol were added to a high-shear wet granulation machine; An aqueous solution of the adhesive containing povidone is added to the dry-mixed powder; After the soft material is prepared, it is transferred to a fluidized bed and dried at 60°C, with a moisture content not exceeding 2.0%. ; Mix the granulated dry granules with the added microcrystalline cellulose and dicalcium phosphate for 15 minutes; Add sodium stearate and mix in a mixer for 10 minutes.

[0027] Comparative Example 2 The composition formulation of Example 1 was modified by removing calcium hydrogen phosphate, and a fixed-dose composition of sitagliptin and metformin was prepared using the preparation steps of Comparative Example 1.

[0028] Experimental Example 1: In vivo pharmacokinetic study The study employed a two-period self-crossover method. Eight rabbits were randomly divided into two groups. Approximately 2 ml of blood from the marginal ear vein was collected before administration as a blank control. The rabbits were administered a single oral dose of Genoda (a commercially available original formulation) containing 50 mg / 850 mg of sitagliptin and metformin, respectively, and the tablets prepared according to Example 1 of this invention (this invention). Blood samples were collected at different time points from 5 min to 48 h to determine the plasma metformin concentration. The pharmacokinetic parameters are shown in Table 1. According to the pharmacokinetic parameters in the table below, the AUC (0-24) of the formulation of this invention was approximately 70% higher than that of the commercially available formulation. Therefore, the amorphous metformin particles prepared using Eudragit L-100 and Eudragit EPO as carrier materials can significantly improve its relative bioavailability.

[0029] Table 1. Comparison of the effects of Example 1 and the commercially available original formulation.

[0030] Test Example 2: Stability Test Tablets prepared in Example 1, Comparative Example 1, and Comparative Example 2 (without added dicalcium phosphate) were placed under accelerated conditions (40°C, 75% relative humidity) for 6 months, and the changes in sitagliptin content, total impurities, and the content of major degradation products (code FP-A) were detected. The results are shown in the table below: Table 2 Comparison of detection results for Example 1, Comparative Example 1, and Comparative Example 2

[0031] As shown in the table above, the addition of inorganic salt dicalcium phosphate reduced the growth rate of total impurities in sitagliptin (FP-A). The sample prepared by mixing and compressing amorphous particles with metformin and then adding sitagliptin (Example 1) showed the slowest impurity growth rate and the best stability.

[0032] Therefore, the present invention employs the above-mentioned fixed-dose composition of sitagliptin and metformin and its preparation method, which has high bioavailability, low hygroscopicity, good stability and is easy to industrialize.

[0033] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A fixed-dose composition of sitagliptin and metformin, characterized in that, The components include the following weight percentages: Sitagliptin: 1%-10%; Metformin hydrochloride: 50%-85%; Adhesives and polymers: 2%-10%; Lubricant: 0.5%-3%; Filler: 10%-40%; Stabilizer: 5%-20%.

2. The fixed-dose composition of sitagliptin and metformin according to claim 1, characterized in that, The stabilizer is a water-insoluble inorganic calcium salt.

3. The fixed-dose composition of sitagliptin and metformin according to claim 1, characterized in that, The amount of stabilizer used is 10%-15% of the total weight of the formulation.

4. The fixed-dose composition of sitagliptin and metformin according to claim 1, characterized in that, The adhesive is polyvinylpyrrolidone.

5. A fixed-dose composition of sitagliptin and metformin according to claim 1, characterized in that, The polymers include one or more of Eudragit L-100 and Eudragit EPO.

6. The fixed-dose composition of sitagliptin and metformin according to claim 1, characterized in that, The lubricant is sodium stearate fumarate.

7. The fixed-dose composition of sitagliptin and metformin according to claim 1, characterized in that, The filler includes mannitol.

8. A method for preparing a fixed-dose composition of sitagliptin and metformin according to any one of claims 1-7, characterized in that, Includes the following steps: Metformin hydrochloride, adhesive, and polymer were dissolved in an ethanol-water solution to prepare a spray solution; Using a packing material as the fluidized bed substrate, the spray solution is atomized and sprayed into the fluidized bed substrate. After drying, amorphous metformin particles are obtained. Sitagliptin, fillers, stabilizers, and amorphous metformin granules were premixed. The premix is ​​mixed with the lubricant to obtain the final mixture, which is then compressed into tablets.

9. A method for preparing a fixed-dose composition of sitagliptin and metformin according to claim 8, characterized in that, The solution preparation rate, which is atomized and sprayed into the fluidized bed substrate, is 0.3~0.6 kg / min; The drying time to obtain amorphous metformin granules after drying is approximately 0.5~1.5 hours, and the temperature is 50~65℃. Premix for 10-20 minutes, and total mix for 5-15 minutes; Tableting speed: 40-80 thousand tablets / hour; pressure: 12-25 kN; tablet hardness: 120-220 N.

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