PHARMACEUTICAL COMPOSITION OF PROLYL HYDROXYLASE INHIBITOR AND PREPARATION METHOD THEREFOR

Abstract

The present application provides a pharmaceutical composition of a prolyl hydroxylase inhibitor and a preparation method therefor. In particular, the present application provides a composition comprising a compound represented by formula (I) or a pharmacologically acceptable salt thereof and at least one water-soluble filler. The composition provided by the present application has a rapid dissolution rate and good stability.

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Claims

1. A pharmaceutical composition, comprising a compound of formula (I) or a pharmacologically acceptable salt thereof and at least one water-soluble filler, ##STR00004##

2. The pharmaceutical composition according to claim 1, wherein the water-soluble filler is a sugar alcohol.

3. The pharmaceutical composition according to claim 1, wherein the water-soluble filler is present in an amount of 15% to 95% relative to the total weight of the composition.

4. The pharmaceutical composition according to claim 1, further comprising at least one additional filler, wherein the additional filler is selected from the group consisting of starch, pregelatinized starch, dextrin, microcrystalline cellulose and calcium hydrogen phosphate.

5. The pharmaceutical composition according to claim 4, wherein the additional filler is present in an amount of 1% to 80% relative to the total weight of the composition.

6. The pharmaceutical composition according to claim 1, further comprising a disintegrant, wherein the disintegrant is one or more selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and crospovidone.

7. The pharmaceutical composition according to claim 6, wherein the disintegrant is present in an amount of 0.1% to 20% relative to the total weight of the composition.

8. The pharmaceutical composition according to claim 1, further comprising a lubricant, wherein the lubricant is one or more selected from the group consisting of talc, magnesium stearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate, sodium lauryl sulfate and hydrogenated vegetable oil, and is present in an amount of 0.1% to 5%, relative to the total weight of the composition.

9. The pharmaceutical composition according to claim 1, wherein the compound of formula (I) or the pharmacologically acceptable salt thereof is present in an amount of 0.1% to 70% relative to the total weight of the composition.

10. The pharmaceutical composition according to claim 1, further comprising a glidant, wherein the glidant is one or more selected from the group consisting of silicon dioxide, corn starch, siliciidoxydum and talc, and is present in an amount of 0.1% to 10% relative to the total weight of the composition.

11. The pharmaceutical composition according to claim 1, wherein the amount of the compound of formula (I) or the pharmacologically acceptable salt thereof in an unit dosage form is 1 to 1000 mg.

12. The pharmaceutical composition according to claim 1, wherein the d0.9 particle size of the compound of formula (I) or the pharmacologically acceptable salt thereof is less than 200 μm determined by a laser particle analyzer.

13. A pharmaceutical composition, comprising the following components: 15% to 35% of a compound of formula (I) or a pharmacologically acceptable salt thereof with a d0.9 particle size distribution of less than 150 μm; 40% to 75% of a sugar alcohol filler; optionally 10% to 50% of microcrystalline cellulose; 0.1% to 20% of a disintegrant, wherein the disintegrant is one or more selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and crospovidone; 0.1% to 5% of a lubricant, wherein the lubricant is one or more selected from the group consisting of talc, magnesium stearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate, sodium lauryl sulfate and hydrogenated vegetable oil; and 0.1% to 10% of a glidant, wherein the glidant is one or more selected from the group consisting of silicon dioxide, corn starch, siliciidoxydum and talc.

14. The pharmaceutical composition according to claim 1, being a tablet or a capsule.

15. The pharmaceutical composition according to claim 14, further comprising a coating layer, wherein the coating material is a gastric-soluble coating, and is specifically one or more selected from the group consisting of polyvinylacetal diethylaminoacetate, Eudragit E series, hydroxypropyl dibutyl cellulose acetate ether, methyl vinyl pyridine, methacrylate and methacrylic acid copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and Opadry® 85G68918, and the weight gain of the coating layer accounts for 1% to 10%.

16. The pharmaceutical composition according to claim 1, wherein the dissolution rate of the composition is ≥75% in 45 minutes, determined according to the Second Method of General Rule 0931 of Volume IV of Chinese Pharmacopoeia 2015 Edition, using phosphate buffer as a dissolution medium at a speed of 75 rpm.

17. A method for preparing the pharmaceutical composition according to claim 1, comprising a step of mixing the compound of formula (I) or the pharmacologically acceptable salt thereof with the water-soluble filler to obtain a mixture, and a step of subjecting the mixture to wet granulation, dry granulation or powder direct compression.

18. The method according to claim 17, optionally comprising a coating step with a gastric-soluble coating material.

19. A method of treating a prolyl hydroxylase-mediated disease in a patient in need thereof, the method comprising administering to the patient the pharmaceutical composition according to claim 1.

Description

DESCRIPTION OF THE DRAWING

[0034] FIG. 1. Dissolution profiles of Examples 1 to 3 and Comparative Examples 1 and 2.

DETAILED DESCRIPTION

[0035] The present invention is further described in detail by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only, and are not intended to limit the scope of the present invention.

Examples 1 to 3, and Comparative Examples 1 and 2

[0036] The materials were weighed accurately. At the beginning, a small amount of lactose (or mannitol or microcrystalline cellulose or anhydrous calcium hydrogen phosphate) was passed through a 40 mesh sieve. Then the compound of formula (I) (active ingredient) and the remaining lactose (or mannitol or microcrystalline cellulose or anhydrous calcium hydrogen phosphate) were mixed and passed through the sieve together. Then microcrystalline cellulose, anhydrous calcium hydrogen phosphate, silicon dioxide and the like were passed through the sieve. The mixture was placed in a suitable mixing bottle and mixed for 15 minutes. Magnesium stearate was added, and the mixture was further mixed for 5 minutes. The mixture was weighed and compressed by a single-punch tableting machine equipped with a ϕ6 mm shallow concave circular punch, the target tablet weight was 100 mg (95 to 105 mg), and the target hardness was 60 N (40 to 80 N). According to the above preparation method, the tablets of Examples 1 to 3 and Comparative Examples 1 and 2 were prepared.

TABLE-US-00001 TABLE 1 Comparative Comparative Ingredients Example 1 Example 2 Example 3 Example 1 Example 2 Active ingredient 2.5 2.5 2.5 2.5 2.5 Lactose 5 0 7.15 0 0 Mannitol 0 5 0 0 0 Microcrystalline cellulose 2.15 2.15 0 2.15 0 Anhydrous calcium 0 0 0 5 7.15 hydrogen phosphate Croscarmellose sodium 0.2 0.2 0.2 0.2 0.2 Siliciidoxydum 0.05 0.05 0.05 0.05 0.05 Magnesium stearate 0.1 0.1 0.1 0.1 0.1 Total 10 g 10 g 10 g 10 g 10 g

Examples 4 to 6, and Comparative Examples 3 and 4

[0037] According to the prescription and preparation method of Example 1, the tablets of Examples 4 to 6 and Comparative Examples 3 and 4 in Table 2 were obtained by controlling the particle size of the active ingredient. The effect of different particle size of the API on product dissolution was investigated.

TABLE-US-00002 TABLE 2 Example Example Example Comparative Comparative 4 5 6 Example 3 Example 4 d0.9 150 49.9 28.9 466 672 particle size distribution of the active ingredient (μm)

Experimental Example 1. Effect of Different Prescriptions on Product Dissolution

[0038] Test solution: According to the dissolution and release test (the Second Method of General Rule 0931 of Volume IV of Chinese Pharmacopoeia 2015 Edition), three tablets were added to 900 ml of phosphate buffer (pH 5.8) (0.5% Tween 80) as a dissolution medium and stirred at a speed of 75 rpm. 2 ml of the solution was collected at 10, 15, 30, 45, 60 and 90 minutes, and filtered through a 0.45 m filter membrane to obtain the test solution.

[0039] Reference solution: An appropriate amount of the active ingredient reference was dissolved in the dissolution medium, and diluted quantitatively to obtain the reference solution. The test solution and reference solution were injected into a liquid chromatograph to record the chromatogram and measure the peak area, respectively. The dissolution amount of each tablet at different times was calculated.

[0040] The dissolution rates of Examples 1 to 3 and Comparative Examples 1 and 2 are shown in Table 3.

TABLE-US-00003 TABLE 3 Cumulative dissolution (%) Experiment No. 10 min 15 min 30 min 45 min 60 min 90 min Example 1 58.54 70.97 86.37 91.24 92.58 93.45 Example 2 64.73 76.82 89.06 92.24 93.14 93.50 Example 3 57.67 71.71 89.71 94.49 95.83 96.05 Comparative Example 1 24.20 30.75 43.30 51.78 58.17 67.05 Comparative Example 2 6.78 8.96 13.23 16.63 19.50 24.43

[0041] The results indicate that the Examples that comprise mannitol or lactose in the prescription have rapid active ingredient dissolution, whereas the Comparative Examples that do not comprise mannitol or lactose have slow and incomplete dissolution. The dissolution profiles are shown in FIG. 1.

[0042] The dissolution rates of Examples 4 to 6 and Comparative Examples 3 and 4 are shown in Table 4.

TABLE-US-00004 TABLE 4 Cumulative dissolution (%) Experiment No. 10 min 15 min 30 min 45 min 60 min 90 min Example 4 42.26 54.20 76.37 87.95 93.69 97.44 Example 5 55.85 69.04 86.77 92.04 93.34 93.98 Example 6 58.82 71.35 86.21 89.59 90.30 90.46 Comparative Example 3 25.85 35.49 58.00 73.99 85.32 97.90 Comparative Example 4 12.70 17.97 30.82 41.29 49.99 63.76

[0043] The experiment results indicate that when the d0.9 particle size distribution of the active ingredient in the prescription is greater than 200 μm, the active ingredient dissolution is slow and incomplete; when d0.9 the particle size distribution of the active ingredient is less than 200 μm, the dissolution rate tends to gradually become rapid as the particle size decreases.

Experimental Example 2: Stability Study

[0044] Tablets of Examples 1 to 3 and Comparative Examples 1 and 2 were left to stand in an open condition, at a temperature of 60° C., or at a temperature of 40° C. and a relative humidity of 75% for 14 days or 30 days, respectively. The formation of total impurities was determined by HPLC method. The results show that all prescriptions are stable under high temperature and high humidity conditions, and there is no obvious difference. The experiment results are shown in Table 5.

TABLE-US-00005 TABLE 5 Main ingredient Total Experiment No. Condition content (%) impurities (%) Example 1  0 d 98.63 1.37 14 d, 60° C. 98.51 1.49 14 d, 40° C., 75% RH 98.69 1.31 30 d, 60° C. 98.53 1.47 30 d, 40° C., 75% RH 98.6 1.40 Example 2  0 d 98.51 1.49 14 d, 60° C. 98.6 1.40 14 d, 40° C., 75% RH 98.61 1.39 30 d, 60° C. 98.42 1.58 30 d, 40° C., 75% RH 98.6 1.40 Example 3  0 d 98.5 1.50 14 d, 60° C. 98.5 1.50 14 d, 40° C., 75% RH 98.63 1.37 30 d, 60° C. 98.46 1.54 30 d, 40° C., 75% RH 98.63 1.37 Comparative  0 d 98.52 1.48 Example 1 14 d, 60° C. 98.46 1.54 14 d, 40° C., 75% RH 98.72 1.28 30 d, 60° C. 98.41 1.59 30 d, 40° C., 75% RH 98.64 1.36 Comparative  0 d 98.62 1.38 Example 2 14 d, 60° C. 98.53 1.36 14 d, 40° C., 75% RH 98.72 1.36 30 d, 60° C. 98.33 1.36 30 d, 40° C., 75% RH 98.64 1.36