Sitagliptin phosphate monohydrate composition and preparation method thereof

Abstract

The invention provides a sitagliptin phosphate monohydrate composition and a preparation method thereof, and belongs to the technical field of medicine preparation. The composition consists of 30 to 35 percent of sitagliptin phosphate monohydrate main drug, microcrystalline cellulose, anhydrous dicalcium phosphate, polyvinylpolypyrrolidone, magnesium stearate, silicon dioxide and a coating agent, the particle size D90 of the raw material medicines of the pharmaceutical composition is less than 12.5 microns, the in-vitro dissolution capacity is fully improved, and the dissolution rate and the dissolution rate of sitagliptin phosphate monohydrate can be effectively improved by selecting auxiliary materials; the prepared sitagliptin phosphate monohydrate pharmaceutical composition is good in stability, high in optical purity, flat and smooth in tablet surface, high in main drug purity, high in optical purity and high in in-vitro dissolution rate under the conditions of high temperature, high humidity and illumination.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and particularly relates to a sitagliptin phosphate monohydrate pharmaceutical composition and a preparation method thereof. Background Art

[0002] In 2009, sitagliptin tablets were approved by NMPA under the trade name Januvia. It is the first DPP-4 inhibitor to be marketed in China and can be used to treat patients with type 2 diabetes. At the same time, sitagliptin phosphate has received widespread attention as a new diabetes treatment drug.

[0003] Chinese patent CN106822017A discloses a sitagliptin phosphate tablet and a preparation method thereof, wherein the composition comprises sitagliptin phosphate, a filler, a binder, a disintegrant and a lubricant, and a finished sitagliptin phosphate composition is obtained by dry granulation combined with coating. CN11206210A reports another dry granulation process of sitagliptin phosphate composition, but the process has an increase in impurities under high temperature and high humidity conditions, and multiple batches of single impurities are greater than 0.30%. CN110559270A reports a pharmaceutical composition and a preparation method, wherein the disclosed preparation method reflects that the coating and the uncoated are compared under the same conditions, and the stability of the coating is greatly improved under high temperature, high humidity and light conditions, but the purity of the 0-day sample is mostly 99% under high temperature, high humidity and light conditions, and there are many impurities.

[0004] Therefore, through prescription improvement and process preparation research, using high-purity sitagliptin phosphate monohydrate as the main drug, preparing stable sitagliptin phosphate monohydrate and solubility under high temperature, high humidity and light conditions has become a technical problem that needs to be solved urgently in this field. Summary of the invention

[0005] The present invention aims to provide a sitagliptin phosphate monohydrate pharmaceutical composition and a preparation method thereof.

[0006] Specifically, the present application is implemented through the following technical solutions:

[0007] First, the present application provides a sitagliptin phosphate monohydrate drug group, the composition includes a plain tablet and a coating agent, the plain tablet is composed of the following weight percentages: 30.0%-35.0% sitagliptin phosphate monohydrate, 29%-43% microcrystalline cellulose as a filler, 3%-5% cross-linked polyvinylpyrrolidone as a disintegrant, 1%-2% silicon dioxide as a glidant, 0.5%-1% magnesium stearate as a lubricant, and the rest is anhydrous calcium dihydrogen phosphate. The sitagliptin phosphate monohydrate is shown in the following formula (I):

[0008]

[0009] The particle size D90 of the active pharmaceutical ingredients in the above-mentioned pharmaceutical composition is less than 12.5 um, thereby fully improving the in vitro dissolution ability. By selecting excipients, the dissolution rate and dissolution speed of sitagliptin phosphate monohydrate can be effectively improved.

[0010] Furthermore, the above-mentioned core tablets are composed of the following raw materials by mass percentage: sitagliptin phosphate monohydrate 32.1%, microcrystalline cellulose 29%-43%, crospovidone 3%-5%, silicon dioxide 1.4%-1.5%, magnesium stearate 0.4%-0.5%, and the balance is calcium dihydrogen phosphate anhydrous; the coating agent accounts for 2.5%-4.5% of the mass of the core tablets.

[0011] Further, the above-mentioned coating agent is composed of the following raw materials by mass percentage: titanium dioxide 15%-25%, polyethylene glycol 5%-15%, talc powder 25%-45%, yellow iron oxide 1-5%, and the balance is polyvinyl alcohol.

[0012] Further, the mass of the coating agent is 2.5%-4.5% of the mass of the core tablets.

[0013] Secondly, the present application provides a preparation method of the above-mentioned sitagliptin phosphate monohydrate pharmaceutical composition, which is specifically as follows:

[0014] a) Pass the main drug sitagliptin phosphate monohydrate through a 120-mesh sieve, and pass the filler microcrystalline cellulose, calcium dihydrogen phosphate anhydrous, crospovidone, and coating agent through an 80-mesh sieve for later use;

[0015] b) Mix sitagliptin phosphate monohydrate, microcrystalline cellulose, calcium dihydrogen phosphate anhydrous, and crospovidone evenly, add them to a granulator for granulation, and then screen them through a 20-mesh sieve; finally, add magnesium stearate and silicon dioxide and mix evenly to obtain a mixed powder;

[0016] c) Press the above-mentioned mixed powder to obtain core tablets with a hardness of 100-130 N;

[0017] d) Coating the core tablets obtained in step c), preheating the core tablets in a rotary coating pan, controlling the temperature at 30-40 °C, and simultaneously spraying deionized water and coating agent powder onto the core tablets in the coating pan using a liquid spray gun and a powder spray gun to obtain coated tablets; place the coated tablets at 30-40 °C for 36-60 h, and while drying, the coating agent solidifies into a film to obtain the sitagliptin phosphate monohydrate pharmaceutical composition. The mass ratio of the sprayed deionized water to the coating agent is 4:1.

[0018] Further, during the granulation of the mixed powder, the feeding speed is 15 rpm, the screening speed is 70 rpm, the liquid pressure is 5.0 MPa, the tableting speed is 12 rpm, and it is placed in an oscillating sieve and screened through a 20-mesh sieve.

[0019] Compared with the existing technologies, the present invention has the following beneficial effects:

[0020] The active molecule sitagliptin phosphate monohydrate used in the present invention is produced by enzymatic preparation, with high purity reaching over 99.8% and high optical purity reaching over 99.6%. The sitagliptin phosphate monohydrate pharmaceutical composition prepared in the examples has good stability under high temperature, high humidity and light conditions, with almost no change in impurities. The dissolution curve is similar to that of the reference sitagliptin phosphate (Januvia), and the tablet surface is smooth, which is suitable for patients to use. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is the content detection spectrum of Example 1 of sitagliptin phosphate monohydrate at 0 day under high temperature;

[0022] Figure 2 It is the content detection spectrum of Example 1 of sitagliptin phosphate monohydrate at 10 days under high temperature;

[0023] Figure 3 It is the optical purity detection spectrum of Example 1 of sitagliptin phosphate monohydrate at 0 day under high temperature;

[0024] Figure 4 It is the optical purity detection spectrum of Example 1 of sitagliptin phosphate monohydrate at 10 days under high temperature;

[0025] Figure 5 It is the photo of the 10 - minute dissolution test of Composition 1 in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0026] The above - mentioned content of the present invention will be further described in detail through the following specific embodiments in the form of examples.

[0027] Main drug and excipients in the examples: Sitagliptin phosphate monohydrate is prepared by the method disclosed in Example 1 of the reference patent CN116694697A; microcrystalline cellulose refers to microcrystalline cellulose PH102, purchased from Asahi Kasei Corporation of Japan, and other excipients are all commercially available.

[0028] Main equipment: Dry granulator: GK25 of Nanjing Honggangsheng Machinery Equipment Factory; Tablet press: ZPS008 of Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd.; Intelligent tablet hardness tester: YD - 35 of Tianjin Tianda Tianfa Technology Co., Ltd.; Friability tester: FT - 2000AE of Tianjin Tianda Tianfa Technology Co., Ltd.; Oscillating sieve: BZ - 200 of Xinxiang Gaofu Screening Machinery Co., Ltd.; Intelligent disintegrator: ZB - 2E of Tianjin Tianda Tianfa Technology Co., Ltd.; Small coating pan: BYF of Yangzhou Fengyihang Film Coating Pan.

[0029] Related substances and content determination conditions: Chromatographic column: Octadecylsilyl silica gel as filler (4.6 * 15 cm, 5 μm), mobile phase: acetonitrile and buffer solution (potassium dihydrogen phosphate solution, pH 2.0) (20:80), wavelength 205 nm, flow rate 1.0 ml / min, column temperature 30 °C

[0030] Examples 1 - 3

[0031] Table 1 Formulation of Sitagliptin Phosphate Monohydrate Pharmaceutical Composition in Examples 1 - 3

[0032]

[0033]

[0034] In Examples 1 - 3, the following preparation method was adopted, including the following steps:

[0035] a) Pass the main drug sitagliptin phosphate monohydrate through a 120 - mesh sieve, and pass the filler microcrystalline cellulose, anhydrous calcium dihydrogen phosphate, crospovidone, magnesium stearate, silicon dioxide, and coating agent through an 80 - mesh sieve respectively, and set aside;

[0036] In this example, the ratio of the coating agent is as follows: by mass percentage, titanium dioxide 15%, polyethylene glycol 10%, talc powder 35%, yellow iron oxide 4%, and the balance is polyvinyl alcohol.

[0037] b) Mix sitagliptin phosphate monohydrate, microcrystalline cellulose, anhydrous calcium dihydrogen phosphate, and crospovidone evenly according to the ratio in Table 1, add them to a granulator for granulation, with a feeding speed of 15 rpm, a screening speed of 70 rpm, and a liquid pressure of 6.8 Mpa, and then screen through a 20 - mesh sieve (oscillating sieve); finally, add magnesium stearate and silicon dioxide and mix evenly to obtain a mixed powder;

[0038] c) Put the mixed powder obtained in step b) into a tablet press for tableting, with the rotation speed of the tablet press being 12 rpm, to obtain plain tablets with a hardness of 110;

[0039] d) Coating the plain tablets obtained in step c): Preheat the plain tablets in a rotating coating pan, control the temperature at 30 - 40 °C, and use a liquid spray gun and a powder spray gun to spray deionized water and coating agent powder onto the plain tablets in the coating pan respectively to obtain coated tablets; the mass ratio of the sprayed deionized water to the coating agent is 4:1; place the coated tablets at 35 °C for curing for 36 h, and wait for the coating agent to cure into a film to obtain the sitagliptin phosphate monohydrate pharmaceutical composition.

[0040] Examples 4 - 6

[0041] Table 2 Formulation of Sitagliptin Phosphate Monohydrate Pharmaceutical Composition in Examples 4 - 6

[0042]

[0043] The preparation methods of the compositions in Examples 4-6 are the same as those in Example 1. However, the main drug, coating weight gain are the same as those in Examples 1-3. The fillers, disintegrants, glidants and lubricants are slightly different, and the specific ratios are shown in Table 2 above.

[0044] The sitagliptin phosphate monohydrate pharmaceutical compositions prepared in Examples 1-6 were detected as follows: Experiment 1. Quality detection

[0045] The sitagliptin phosphate monohydrate pharmaceutical compositions prepared in Examples 1-6 were subjected to friability, hardness, coating rate, disintegration time limit and content detection. The detection results are shown in Table 3 below:

[0046] Table 3 Detection results of the compositions in Examples 1-6

[0047] Group Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Friability 0 0 0.02％ 0.01％ 0 0 Hardness 110N 115N 112N 105N 120N 115N Coating rate 95％ 96％ 96％ 97％ 95％ 96％ Disintegration time limit 30s 35s 20s 25s 40s 30s Content 99.9％ 100.2％ 101.5％ 101.0％ 99.1％ 98.8％

[0048] As can be seen from the above table, the tablets have low friability, a hardness of about 110 N, a high coating rate of over 95%. They disintegrate within 40 s, and the content is about 100%, which is basically equivalent to the disintegration time limit of Januvia.

[0049] Experiment 2. Stability test

[0050] This experiment refers to the relevant requirements of the Guidelines for Stability Testing of Drug Substances and Preparations under the General Principles 9000, Part IV of the Chinese Pharmacopoeia 2020 Edition.

[0051] High temperature test: The sitagliptin phosphate monohydrate pharmaceutical compositions prepared in Examples 1-6 were placed in an opener and stored at 60 °C for 10 days. Samples were taken on the 5th and 10th days respectively and compared with the data on day 0 to measure the sitagliptin content.

[0052] High humidity test: The sitagliptin phosphate monohydrate pharmaceutical compositions prepared in Examples 1-6 were placed in a constant temperature and airtight dryer and stored at 25 °C under the condition of relative humidity of 75% ± 5% (saturated NaCl solution: relative humidity 75% ± 1%) for 10 days. Samples were taken on the 5th and 10th days respectively and compared with the data on day 0 to measure the sitagliptin content.

[0053] Light test: The sitagliptin phosphate monohydrate pharmaceutical compositions prepared in Examples 1-6 were placed under the condition of illuminance of (4500 ± 500) lx and stored for 10 days. Samples were taken on the 5th and 10th days respectively and compared with the data on day 0 to measure the sitagliptin content and optical purity.

[0054] The detection results are shown in Table 4:

[0055] Table 4 Stability detection results

[0056]

[0057]

[0058] Figure 1 The test result of the sitagliptin phosphate monohydrate content at high temperature for 0 days in the composition prepared in Example 1 is: Figure 2 The test result of sitagliptin phosphate monohydrate content in the composition prepared in Example 1 at high temperature for 10 days is: Figure 3 This is the optical test result of the composition prepared in Example 1 at high temperature for 0 days. Figure 4 This is the optical test result of the composition prepared in Example 1 at high temperature for 10 days.

[0059] Combined with Figures 1 - 4 As can be seen from the above table, under the conditions of high temperature, high humidity and light exposure test, the content of sitagliptin phosphate monohydrate in the compositions prepared in Examples 1-6 is stable and basically does not change; the optical purity is high, and under the conditions of high temperature, high humidity and light exposure test, it basically does not change, and has higher purity and optical purity than the main drug of Januvia.

[0060] Experiment 3: Dissolution Test

[0061] Test method: This test refers to the relevant requirements of the second method for dissolution and release determination under the guidance of Part IV 0931 of the 2020 edition of the Chinese Pharmacopoeia. Use 1000ml of water, pH 6.8 (sodium dihydrogen phosphate and disodium hydrogen phosphate) as the dissolution medium, the speed is 50rpm, the temperature is 37±0.5℃, operate according to the law, and sample 10ml at 5min, 10min, 15min, 30min, 45min and 60min respectively. Measure 5 tablets for each example and calculate the dissolution of each example.

[0062] Control drug: Sitagliptin phosphate (Janovi), 100 mg, approval number: National Medicine Standard H20237004, product batch number: X024421; Marketing authorization holder: Hangzhou Merck Pharmaceuticals Co., Ltd., listed company name: Hangzhou Merck Pharmaceuticals Co., Ltd. Production address: No. 199, Wenhai North Road, Hangzhou Economic Development Zone, Hangzhou.

[0063] Table 5 Dissolution test results under water medium conditions (dissolution, water medium, 50rpm)

[0064] Dissolution rate Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Reference drug 5 min 42.1 42.6 44.8 47.2 44.6 45.8 46.8 10 min 62.1 58.2 58.4 60.8 60.2 60.4 61.5 15 min 67.4 70.8 71.2 69.2 66.8 68.4 73.4 30 min 87.8 86.4 87.6 88.4 89.2 91.6 90.2 45 min 90.6 89.5 94.1 93.5 92.4 90.8 94.8 60 min 95.6 97.2 94,8 95.8 97.3 96.8 98.2

[0065] Table 6 Dissolution test results under pH 6.8 (dissolution, pH 6.8 medium, 50 rpm)

[0066] Dissolution rate Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Reference drug 5 min 43.2 46.8 44.2 45.1 48.3 45.8 47.8 10 min 62.8 61.2 60.8 64.1 63.2 61.8 62.4 15 min 70.3 71.1 73.2 72.8 75.4 76.2 74.5 30 min 91.0 87.2 88.6 89.2 90.4 92.4 91.3 45 min 94.1 94.8 93.8 95.6 92.7 96.1 95.2 60 min 98.4 96.4 97.2 96.8 97.3 98.2 98.6

[0067] Figure 5 Photograph of the composition prepared in Example 1 at the 10th minute during the dissolution test in an aqueous medium.

[0068] As can be seen from the dissolution in the aqueous medium and the medium of pH 6.8 in Tables 5 and 6, within 30 minutes, the dissolution of sitagliptin phosphate monohydrate reached more than 85%, which was comparable to that of the reference drug; and it was basically completely dissolved within 60 minutes. In the two media, the dissolution of the compositions of Examples 1-6 was basically similar to that of the reference drug.

Claims

1. A sitagliptin phosphate monohydrate composition, characterized in that, The described composition consists of a core tablet and a coating agent; the core tablet consists of the following raw materials, by mass percentage: sitagliptin phosphate monohydrate 30.0% - 35.0%, microcrystalline cellulose 29% - 43%, crospovidone 3% - 5%, silicon dioxide 1% - 2%, magnesium stearate 0.5% - 1%, and the balance is calcium dihydrogen phosphate anhydrous; the structural formula of sitagliptin phosphate monohydrate is as shown in formula (I): The coating agent consists of the following raw materials, by mass percentage: titanium dioxide 15% - 25%, polyethylene glycol 5% - 15%, talc powder 25% - 45%, yellow iron oxide 1 - 5%, and the balance is polyvinyl alcohol.

2. The sitagliptin phosphate monohydrate composition according to claim 1, characterized in that, The core tablet consists of the following raw materials, by mass percentage: sitagliptin phosphate monohydrate 32.1%, microcrystalline cellulose 29% - 43%, crospovidone 3% - 5%, silicon dioxide 1.4% - 1.5%, magnesium stearate 0.4% - 0.5%, and the balance is calcium dihydrogen phosphate anhydrous.

3. The sitagliptin phosphate monohydrate composition according to claim 1, characterized in that, The mass of the coating agent is 2.5% - 4.5% of the mass of the core tablet.

4. The preparation method of the sitagliptin phosphate monohydrate composition according to any one of claims 1-3, characterized in that, The steps are as follows: a) Pass sitagliptin phosphate monohydrate through a 120 - mesh sieve, and pass microcrystalline cellulose, calcium dihydrogen phosphate anhydrous, crospovidone, and the coating agent through an 80 - mesh sieve, and set aside; b) Mix sitagliptin phosphate monohydrate, microcrystalline cellulose, calcium dihydrogen phosphate anhydrous, and crospovidone evenly and granulate, then screen the granules through a 20 - mesh sieve, and finally add magnesium stearate and silicon dioxide and mix evenly to obtain a mixed powder; c) Press the mixed powder to obtain a core tablet with a hardness of 100 - 130 N; d) Coat the core tablet with the coating agent to obtain the sitagliptin phosphate monohydrate composition.

5. The preparation method according to claim 4, wherein The coating means placing the core tablet in a rotary coating pan, and spraying deionized water and the coating agent on the core tablet simultaneously at a temperature of 30 - 40 °C to obtain a coated tablet; placing the coated tablet at a temperature of 30 - 40 °C until the coating agent cures into a film.

6. The preparation method according to claim 5, characterized in that, The mass ratio of the sprayed deionized water to the coating agent is 4:1.

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