HS-25 tablet and preparation method therefor

Abstract

An HS-25 tablet, an HS-25 solid dispersion composition, a preparation method therefor and usage thereof. The HS-25 tablet is made by using HS-25 and excipients for wet granulation, drying, granulating and tablet pressing.

Claims

1. An hyzetimibe tablet, comprising hyzetimibe, a filler, a binder, a disintegrating agent and a lubricant, wherein hyzetimibe accounts for 1-20% by weight of the tablet wherein the binder is povidone.

2. The hyzetimibe tablet according to claim 1, wherein the filler is at least one of lactose, microcrystalline cellulose and pregelatinized starch; the disintegrating agent is at least one of crospovidone and croscarmellose sodium; and the lubricant is at least one of magnesium stearate and talc.

3. The hyzetimibe tablet according to claim 1, further comprising a stabilizer and/or surfactant.

4. The hyzetimibe tablet according to claim 3, wherein the stabilizer is at least one of butylated hydroxyanisole and butylated hydroxytoluene; and the surfactant is at least one of sodium dodecylsulfate and polysorbate.

5. The hyzetimibe tablet according to claim 1, comprising 30-60% by weight of lactose, 20-60% by weight of microcrystalline cellulose, 1-5% by weight of povidone, 1-10% by weight of crospovidone or croscarmellose sodium, 0-0.1% by weight of butylated hydroxytoluene, 0-5% by weight of sodium dodecylsulfate, and 0.5-2% by weight of magnesium stearate.

6. The hyzetimibe tablet according to claim 5, comprising 0.005-0.1% by weight of butylated hydroxytoluene.

7. The hyzetimibe tablet according to claim 5, comprising 1-5% by weight of sodium dodecylsulfate.

8. The hyzetimibe tablet according to claim 1, which can be prepared by granulating using water, alcohol, acetone or a similar solvent, or a mixture thereof, and then tabletting.

9. The hyzetimibe tablet according to claim 1, comprising a hyzetimibe solid dispersion comprising hyzetimibe and povidone.

10. A hyzetimibe solid dispersion composition, comprising hyzetimibe and povidone.

11. A hyzetimibe tablet, comprising the hyzetimibe solid dispersion composition of claim 10.

12. A method for preparing a hyzetimibe solid formulation, comprising using the hyzetimibe solid dispersion composition of claim 10.

13. The method according to claim 12, wherein the solid formulation is selected from the group consisting of tablet, capsule, granule and powder.

14. A method for preparing the hyzetimibe solid dispersion composition of claim 10, comprising the following step: dissolving hyzetimibe in an organic solvent comprising povidone.

15. The preparation method according to claim 14, further comprising pouring or spraying the obtained hyzetimibe solution into adjuvant materials.

16. The preparation method according to claim 14, wherein the organic solvent is selected from the group consisting of ethanol, isopropanol, and a mixture thereof with water.

17. A method for preparing the hyzetimibe tablet of claim 8, comprising the following steps: (1) mixing hyzetimibe with lactose, microcrystalline cellulose, sodium dodecylsulfate and croscarmellose sodium homogeneously; (2) dissolving povidone in water; (3) adding the povidone solution of step (2) into the mixture of step (1), granulating, drying, and sizing; and (4) mixing the sized particles in step (3) with magnesium stearate homogeneously, and tabletting.

18. The preparation method for the hyzetimibe tablet according to claim 17, wherein hyzetimibe used in the preparation is hyzetimibe crystal form I.

19. The preparation method for the hyzetimibe tablet according to claim 17, wherein hyzetimibe used in the preparation has a particle size of 1 μm≤D90≤100 μm, and preferably 1 μm≤D90≤50 μm.

20. A method for preparing the hyzetimibe tablet according to claim 8, comprising the following steps: (1) mixing lactose, microcrystalline cellulose, sodium dodecylsulfate and crospovidone homogeneously, or mixing lactose, microcrystalline cellulose and crospovidone homogeneously; (2) dissolving hyzetimibe, povidone and butylated hydroxytoluene in an alcohol solvent, or dissolving hyzetimibe and povidone in an alcohol solvent; (3) adding the solution obtained in step (2) into the mixture obtained in step (1), granulating, drying, and sizing; and (4) mixing the particles obtained in step (3) with magnesium stearate homogeneously, and tabletting.

21. The preparation method for the hyzetimibe tablet according to claim 20, wherein the alcohol solvent used in the preparation method is an aqueous ethanol solution, preferably in a concentration of ≥60% (w/w), more preferably ≥75% (w/w), and most preferably 80-90% (w/w), and in an amount of 30-50% (w/w) of prescription amount, and more preferably 35-45% (w/w) of prescription amount.

22. The preparation method for the hyzetimibe tablet according to claim 20, wherein in the preparation method, the weight ratio of hyzetimibe to povidone is in a range of 10:1-1:1, and more preferably 5:1-5:3.

23. The preparation method for the hyzetimibe tablet according to claim 20, wherein the granulating includes granulating using a high-speed stirring pelletizer or fluidized bed.

24. The preparation method for the hyzetimibe tablet according to claim 20, wherein in the prepared hyzetimibe tablet, more than 90% of hyzetimibe is present in an amorphous form.

25. A hyzetimibe tablet prepared by the preparation method according to claim 17.

26. The hyzetimibe tablet according to claim 1, comprising 5-20 mg of hyzetimibe in each dosage unit.

27. The hyzetimibe tablet according to claim 26, comprising 5 mg, 10 mg or 20 mg of hyzetimibe in each dosage unit.

28. The hyzetimibe tablet according to claim 26, comprising, in each dosage unit, 20-250 mg of lactose, 20-200 mg of microcrystalline cellulose, 1-10 mg of croscarmellose sodium or 5-30 mg of crospovidone, 1-15 mg of povidone K30, 0-0.2 mg of butylated hydroxytoluene, 0-15 mg of sodium dodecylsulfate, and 0.5-10 mg of magnesium stearate.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1: XRD pattern of hyzetimibe placebo.

(2) FIG. 2: XRD pattern of hyzetimibe bulk drug (crystal form I).

(3) FIG. 3: XRD pattern of a mixture of hyzetimibe placebo and hyzetimibe bulk drug (crystal form I).

(4) FIG. 4: XRD pattern of a hyzetimibe tablet with an API concentration of 20% at 0 month.

(5) FIG. 5: XRD pattern of a hyzetimibe tablet with an API concentration of 20% at 3 months.

(6) FIG. 6: XRD pattern of a hyzetimibe tablet with an API concentration of 20% at 9 months.

DETAILED DESCRIPTION

(7) The present disclosure will be described in detail below in combination with Examples. It must be pointed out that the following examples are only used to illustrate the present disclosure, not to limit the present disclosure. The experimental methods in the following examples wherein specific conditions are not noted mean conventional methods and conditions, or they can be selected according to product specifications.

(8) The hyzetimibe bulk drug of the present disclosure was provided by Zhejiang Hisun Pharmaceutical Co., Ltd. The hyzetimibe bulk drug is in crystal type I, and the preparation therefor can be found in WO2014036956.

Example 1

(9) A hyzetimibe tablet (aqueous granulation), strength: 10 mg, weighing 100 mg per tablet. The prescription composition (in g) is as follows:

(10) TABLE-US-00001 hyzetimibe 10.00 lactose monohydrate 200 mesh 39.75 microcrystalline cellulose 101 39.75 croscarmellose sodium 5.00 povidone K30 2.50 sodium dodecylsulfate 2.00 magnesium stearate 1.00 Total 1000 tablets

(11) Preparation Method:

(12) 1. sieving the hyzetimibe bulk drug (unmicronized), lactose monohydrate 200 mesh, microcrystalline cellulose 101, sodium dodecylsulfate, and croscarmellose sodium through a 40 mesh screen, and then premixing;

(13) 2. dissolving povidone K30 in purified water (30% of prescription amount) for later use;

(14) 3. adding the povidone K30 solution of step 2 into the mixture of step 1, granulating, and sizing wet particles using a 1.0 mm screen;

(15) 4. placing the wet particles in a fluidized bed set at an inlet air temperature of 55-65° C., and drying;

(16) 5. sizing through the 1.0 mm screen;

(17) 6. adding magnesium stearate and mixing; and

(18) 7. tabletting.

Example 2

(19) A hyzetimibe tablet (aqueous granulation), strength: 10 mg, weighing 100 mg per tablet. The prescription composition (in g) is as follows:

(20) TABLE-US-00002 hyzetimibe 10.00 lactose monohydrate 200 mesh 39.75 microcrystalline cellulose 101 39.75 croscarmellose sodium 5.00 povidone K30 2.50 sodium dodecylsulfate 2.00 magnesium stearate 1.00 total 1000 tablets

(21) Preparation Method:

(22) The hyzetimibe bulk drug was pulverized by a jet mill, and the preparation method was the same as in Example 1.

Example 3

(23) A hyzetimibe tablet (alcohol granulation prescription), strength: 10 mg, weighing 200 mg per tablet. The prescription composition (in g) is as follows:

(24) TABLE-US-00003 hyzetimibe 10.00 lactose monohydrate 200 mesh 113.96 microcrystalline cellulose 101 60.00 povidone K30 4.00 crospovidone XL 10.00 butylated hydroxytoluene 0.04 magnesium stearate 2.00 total 1000 tablets

(25) Preparation Method:

(26) 1. sieving lactose monohydrate 200 mesh, microcrystalline cellulose 101 and crospovidone XL through a 40 mesh screen, and then premixing;

(27) 2. dissolving butylated hydroxytoluene, povidone K30 and hyzetimibe in 85% (w/w) aqueous ethanol solution (35% of prescription amount) for later use as a binder solution;

(28) 3. adding the binder solution of step 2 into the mixture of step 1, granulating, and sizing wet particles using a 1.0 mm screen;

(29) 4. placing the wet particles in an oven set at a temperature of 40-50° C., and drying;

(30) 5. sizing through the 1.0 mm screen;

(31) 6. adding magnesium stearate and mixing; and

(32) 7. tabletting.

Example 4

(33) A hyzetimibe tablet, strength: 5 mg, weighing 100 mg per tablet. The prescription composition (in g) is as follows:

(34) TABLE-US-00004 hyzetimibe 5.00 lactose monohydrate 200 mesh 57.98 microcrystalline cellulose 101 30.00 povidone K30 1.00 crospovidone XL 5.00 butylated hydroxytoluene 0.02 magnesium stearate 1.00 total 1000 tablets

(35) The preparation method was the same as Example 3.

Example 5

(36) A hyzetimibe tablet, strength: 5 mg, weighing 100 mg per tablet. The prescription composition (in g) is as follows:

(37) TABLE-US-00005 hyzetimibe 5.00 lactose monohydrate 200 mesh 53.98 microcrystalline cellulose 101 30.00 povidone K30 5.00 crospovidone XL 5.00 butylated hydroxytoluene 0.02 magnesium stearate 1.00 total 1000 tablets

(38) The preparation method was the same as Example 3.

Example 6

(39) A hyzetimibe tablet, strength: 5 mg, weighing 100 mg per tablet. The prescription composition (in g) is as follows:

(40) TABLE-US-00006 hyzetimibe 5.00 lactose monohydrate 200 mesh 56.98 microcrystalline cellulose 101 30.00 povidone K30 2.00 crospovidone XL 5.00 butylated hydroxytoluene 0.02 magnesium stearate 1.00 total 1000 tablets

(41) The preparation method was the same as Example 3.

Example 7

(42) A hyzetimibe tablet, strength: 5 mg, weighing 100 mg per tablet. The prescription composition (in g) is as follows:

(43) TABLE-US-00007 hyzetimibe 5.00 lactose monohydrate 200 mesh 54.98 microcrystalline cellulose 101 30.00 povidone K30 2.00 sodium dodecylsulfate 2.00 crospovidone XL 5.00 butylated hydroxytoluene 0.02 magnesium stearate 1.00 total 1000 tablets

(44) Preparation Method:

(45) 1. sieving lactose monohydrate 200 mesh, microcrystalline cellulose 101, crospovidone XL, and sodium dodecylsulfate through a 40 mesh screen, and then premixing;

(46) 2. dissolving butylated hydroxytoluene, povidone K30 and hyzetimibe in 85% (w/w) aqueous ethanol solution (35% of prescription amount) for later use as a binder solution;

(47) 3. adding the binder solution of step 2 into the mixture of step 1, granulating, and sizing wet particles using a 1.0 mm screen;

(48) 4. placing the wet particles in an oven set at a temperature of 40-50° C., and drying;

(49) 5. sizing through the 1.0 mm screen;

(50) 6. adding magnesium stearate and mixing; and

(51) 7. tabletting.

Example 8

(52) A hyzetimibe tablet, strength: 10 mg, 200 mg per tablet. The prescription composition (in g) is as follows:

(53) TABLE-US-00008 hyzetimibe 10.00 lactose monohydrate 200 mesh 109.96 microcrystalline cellulose 101 60.00 povidone K30 4.00 sodium dodecylsulfate 4.00 crospovidone XL 10.00 butylated hydroxytoluene 0.04 magnesium stearate 2.00 total 1000 tablets

(54) The preparation method was the same as Example 7.

Example 9

(55) A hyzetimibe tablet, strength: 20 mg, 400 mg per tablet. The prescription composition (in g) is as follows:

(56) TABLE-US-00009 hyzetimibe 20.00 lactose monohydrate 200 mesh 219.92 microcrystalline cellulose 101 120.00 povidone K30 8.00 sodium dodecylsulfate 8.00 crospovidone XL 20.00 butylated hydroxytoluene 0.08 magnesium stearate 4.00 total 1000 tablets

(57) The preparation method was the same as Example 7.

Example 10

(58) A hyzetimibe tablet, strength: 20 mg, 400 mg per tablet. The prescription composition (in g) is as follows:

(59) TABLE-US-00010 hyzetimibe 20.00 lactose monohydrate 200 mesh 220.00 microcrystalline cellulose 101 120.00 povidone K30 8.00 sodium dodecylsulfate 8.00 crospovidone XL 20.00 magnesium stearate 4.00 total 1000 tablets

(60) Preparation Method:

(61) 1. sieving lactose monohydrate 200 mesh, microcrystalline cellulose 101, crospovidone XL, and sodium dodecylsulfate through a 40 mesh screen, and then premixing;

(62) 2. dissolving povidone K30 and hyzetimibe in 85% (w/w) aqueous ethanol solution (35% of prescription amount) for later use as a binder solution;

(63) 3. adding the binder solution of step 2 into the mixture of step 1, granulating, and sizing wet particles using a 1.0 mm screen;

(64) 4. placing the wet particles in an oven set at a temperature of 40-50° C., and drying;

(65) 5. sizing through the 1.0 mm screen;

(66) 6. adding magnesium stearate and mixing; and

(67) 7. tabletting.

Example 11

(68) A hyzetimibe tablet, strength: 20 mg, 100 mg per tablet. The prescription composition (in g) is as follows:

(69) TABLE-US-00011 hyzetimibe 20.00 lactose monohydrate 200 mesh 47.98 microcrystalline cellulose 101 25.27 povidone K30 1.68 crospovidone XL 4.21 butylated hydroxytoluene 0.02 magnesium stearate 0.84 total 1000 tablets

(70) Preparation Method:

(71) 1. sieving lactose monohydrate 200 mesh, microcrystalline cellulose 101 and crospovidone XL through a 40 mesh screen, and then premixing;

(72) 2. dissolving butylated hydroxytoluene, povidone K30 and hyzetimibe in 85% (w/w) aqueous ethanol solution for later use as a binder solution;

(73) 3. adding the binder solution of step 2 into the mixture of step 1, granulating, and sizing wet particles using a 1.0 mm screen;

(74) 4. placing the wet particles in an oven set at a temperature of 40-50° C., and drying;

(75) 5. sizing through the 1.0 mm screen;

(76) 6. adding magnesium stearate and mixing; and

(77) 7. tabletting.

Example 12

(78) Hyzetimibe placebo, 400 mg per tablet. The prescription composition (in g) is as follows:

(79) TABLE-US-00012 microcrystalline cellulose 101 20.00 lactose monohydrate 200 mesh 219.92 microcrystalline cellulose 101 120.00 povidone K30 8.00 sodium dodecylsulfate 8.00 crospovidone XL 20.00 butylated hydroxytoluene 0.08 magnesium stearate 4.00 total 1000 tablets

(80) Preparation Method:

(81) 1. sieving lactose monohydrate 200 mesh, microcrystalline cellulose 101, crospovidone XL, and sodium dodecylsulfate through a 40 mesh screen, and then premixing;

(82) 2. dissolving butylated hydroxytoluene and povidone K30 in 85% (w/w) aqueous ethanol solution (35% of prescription amount) for later use as a binder solution;

(83) 3. adding the binder solution of step 2 into the mixture of step 1, granulating, and sizing wet particles using a 1.0 mm screen;

(84) 4. placing the wet particles in an oven set at a temperature of 40-50° C., and drying;

(85) 5. sizing through the 1.0 mm screen;

(86) 6. adding magnesium stearate and mixing; and

(87) 7. tabletting.

Test Example 1

(88) After oral administration of tablets prepared in Example 1 and Example 2 to male Beagle dogs, the pharmacokinetic characteristics thereof in dogs were investigated. The data from the animal experiment is shown in Table 1 and Table 2.

(89) TABLE-US-00013 TABLE 1 Pharmacokinetic parameters of hyzetimibe after oral administration of 10 mg/kg hyzetimibe tablets of Example 1 (aqueous granulation) to male Beagle dogs Coefficient Measured value Mean of Pharmacokinetic Dog#7- Dog#8- Dog#9- Dog#10- Dog#11- Dog#12- value Standard variation parameters 8337022 8338354 8336807 8337404 8341924 8343552 (ng/ml) deviation (%) T.sub.max (hr) 12.0 4.00 24.0 8.00 8.00 12.0 11.3 6.89 60.8 C.sub.max (ng/ml) 1.61 1.48 2.69 4.60 0.757 1.53 2.11 1.37 64.7 AUC.sub.last 26.9 12.5 48.0 55.9 13.2 32.6 31.5 17.8 56.4 (hr*ng/ml)

(90) TABLE-US-00014 TABLE 2 Pharmacokinetic parameters of hyzetimibe after oral administration of 10 mg/kg hyzetimibe tablets of Example 2 (micronization and aqueous granulation prescription) to male Beagle dogs Coefficient Measured value Mean of Pharmacokinetic Dog#1- Dog#2- Dog#3- Dog#4- Dog#5- Dog#6- value Standard variation parameters 8337022 8338354 8336807 8337404 8341924 8343552 (ng/ml) deviation (%) T.sub.max (hr) 2.00 2.00 12.0 24.0 2.00 24.0 11.0 10.8 98.1 C.sub.max (ng/ml) 49.4 3.29 2.91 1.30 1.35 5.43 10.6 19.1 180 AUC.sub.last 424 20.4 38.0 34.2 15.4 106 106 159 150 (hr*ng/ml)

(91) Conclusion: The tablets of Example 2 (comprising micronizing the hyzetimibe bulk drug) can significantly improve the bioavailability of hyzetimibe in vivo.

Test Example 2

(92) After oral administration of tablets prepared in Example 3 to male Beagle dogs, the pharmacokinetic characteristics thereof in dogs were investigated. The data from the animal experiment is shown in Table 3.

(93) TABLE-US-00015 TABLE 3 Pharmacokinetic parameters of hyzetimibe after oral administration of 10 mg/kg hyzetimibe tablets of Example 3 (alcohol granulation prescription) to male Beagle dogs Coefficient Measured value Mean of Pharmacokinetic Dog#1- Dog#2- Dog#3- Dog#4- Dog#5- Dog#6- value Standard variation parameters 8337022 8338354 8336807 8337404 8341924 8343552 (ng/ml) deviation (%) T.sub.max(hr) 2.00 2.00 12.0 12.0 24.0 12.0 10.7 8.16 76.5 C.sub.max (ng/ml) 73.7 2.29 2.71 3.38 1.79 7.52 15.2 28.7 189 AUC.sub.last 570 24.7 46.8 57.0 38.7 140 146 212 145 (hr*ng/ml)

(94) As compared to the tablets of Examples 1 and 2 (both aqueous granulation prescription for hyzetimibe), the tablets of Example 3 (alcohol granulation prescription) can result in a higher bioavailability of hyzetimibe in vivo.

Test Example 3

(95) Study on the Stability of Hyzetimibe Tablets (Strength: 10 mg)

(96) After the tablets prepared in Example 3 was subjected to aluminum-plastic packaging, they were packaged in a blank middle sealing bag (containing 2 g of desiccant therein) and placed under the condition of temperature of 25±2° C. and humidity (RH) of 60%±5% for stability study. The test results are shown in Table 4.

(97) TABLE-US-00016 TABLE 4 Stability data of hyzetimibe tablets (strength: 10 mg) Storage condition: 25 ± 2° C., RH 60% ± 5% Packaging condition: aluminum plastic panel plus blank middle sealing bag, containing 2 g of desiccant therein 0 3 6 9 12 18 24 Test Items month months months months months months months Content (%) Hyzetimibe 102.0 104.3 102.8 101.7 102.5 102.7 102.9 Related Single Largest 0.05 0.08 0.05 0.06 0.06 0.06 0.04 Substances Impurity (%) (Hyzetimibe) Total Impurities 0.10 0.19 0.15 0.17 0.17 0.20 0.22 (Hyzetimibe) Dissolution (%) Hyzetimibe 83 83 85 84 80 83 88

(98) The results show that after storage at 25±2° C. and RH 60% 5% for 24 months, the content and dissolution of the hyzetimibe tablet (10 mg) did not change significantly, and the impurities increased slightly, indicating that the sample was stable.

Test Example 4

(99) Stability Data from the Stability Study on Hyzetimibe Tablets (Strength: 5 mg)

(100) After the tablets prepared in Example 6 were subject to aluminum-plastic packaging, they were packaged in a blank middle sealing bag (containing 2 g of desiccant therein) and placed under the condition of temperature of 25±2° C. and humidity (RH) of 60%±5% for stability study. The test results are shown in Table 5.

(101) TABLE-US-00017 TABLE 5 Stability data of hyzetimibe tablets (strength: 5 mg) Storage condition: 25 ± 2° C., RH 60% ± 5% Packaging condition: aluminum plastic panel plus blank middle sealing bag, containing 2 g of desiccant therein 0 3 6 9 12 18 24 Test items month months months months months months months Content (%) Hyzetimibe 101.7 100.6 100.8 101.1 99.7 101.0 101.6 Related Single largest 0.05 0.07 0.05 0.06 0.06 0.07 0.06 substances impurity (%) (hyzetimibe) Total impurities 0.09 0.18 0.14 0.18 0.17 0.18 0.21 (hyzetimibe) Dissolution (%) Hyzetimibe 85 83 84 82 87 84 85

(102) The results show that after storage at 25±2° C. and RH 60%±5% for 24 months, the content and dissolution of the hyzetimibe tablet (5 mg) do not change significantly, and the impurities increase slightly, indicating that the sample is stable.

Test Example 5

(103) Stability Data from the Stability Study on Hyzetimibe Tablets (Strength: 10 mg)

(104) After the tablets prepared in Example 8 were subject to aluminum-plastic packaging, they were packaged in a blank middle sealing bag (containing 2 g of desiccant therein) and placed under the condition of temperature of 25±2° C. and humidity (RH) of 60%±5% for stability study. The test results are shown in Table 6.

(105) TABLE-US-00018 TABLE 6 Stability data of hyzetimibe tablets (strength: 10 mg) Storage condition: 25 ± 2° C., RH 60% ± 5% Packaging condition: aluminum plastic panel plus blank middle sealing bag, containing 2 g of desiccant therein 0 3 6 9 12 18 24 36 Test items month months months months months months months months Content (%) Hyzetimibe 99.6 101.0 98.5 99.4 97.8 98.7 99.6 100.9 Related Single largest 0.11 0.12 0.15 0.11 0.11 0.11 0.11 0.12 substances impurity (%) (hyzetimibe) Total impurities 0.11 0.16 0.22 0.15 0.16 0.15 0.18 0.23 (hyzetimibe) Dissolution (%) Hyzetimibe 86 85 85 88 87 88 87 87

(106) The results show that after storage at 25±2° C. and RH 60% 5% for 36 months, the content and dissolution of the hyzetimibe tablet (10 mg) did not change significantly, and the impurities increased slightly, indicating that the sample was stable.

Test Example 6

(107) Stability Data from the Stability Study on Hyzetimibe Tablets (Strength: 20 mg)

(108) After the tablets prepared in Example 9 were subject to aluminum-plastic packaging, they were packaged in a blank middle sealing bag (containing 2 g of desiccant therein) and placed under the condition of temperature of 25±2° C. and humidity (RH) of 60% 5% for stability study. The test results are shown in Table 7.

(109) TABLE-US-00019 TABLE 7 Stability data of hyzetimibe tablets (strength: 20 mg) Storage condition: 25 ± 2° C., RH 60% ± 5% Packaging condition: aluminum plastic panel plus blank middle sealing bag, containing 2 g of desiccant therein 0 3 6 9 12 18 24 36 Test items month months months months months months months months Content (%) Hyzetimibe 101.6 100.5 102.7 101.9 101.8 100.9 102.3 101.6 Related Single largest 0.27 0.25 0.28 0.26 0.27 0.27 0.27 0.26 substances impurity (%) (hyzetimibe) Total impurities 0.54 0.55 0.70 0.61 0.76 0.76 0.76 0.71 (hyzetimibe) Dissolution (%) Hyzetimibe 86 89 89 89 89 88 89 88

(110) The results show that after storage at 25±2° C. and RH 60% 5% for 36 months, the content and dissolution of the hyzetimibe tablet (20 mg) did not change significantly, and the impurities increased slightly, indicating that the sample was stable.

Test Example 7

(111) Stability Data of Hyzetimibe Tablets without BHT

(112) After the tablets of Example 9 and Example 10 were subject to aluminum-plastic packaging, they were packaged in a blank middle sealing bag (containing 2 g of desiccant therein) and placed under the condition of temperature of 40±2° C. and humidity (RH) of 75%±5% for stability study. The test results are shown in Table 8.

(113) TABLE-US-00020 TABLE 8 Stability data of hyzetimibe tablets (strength: 20 mg) Test items 0 month 3 months Tablets prepared Specific impurities 0.05 0.18 in Example 10 Tablets prepared Specific impurities 0.00 0.03 in Example 9

Test Example 8

(114) Effect of Sodium Dodecylsulfate (SDS) on the Dissolution of Hyzetimibe Tablets

(115) Dissolution test: paddle method, dissolution medium: 0.1 N hydrochloric acid solution containing 0.5% SDS, rotary speed: 50 rpm, medium volume: 900 mL

(116) The dissolution of the tablets of Example 3 and Example 8 were measured respectively, and the results are shown in Table 9.

(117) TABLE-US-00021 TABLE 9 Comparison of dissolution data of hyzetimibe tablets (strength: 10 mg) Time (min) 5 10 15 20 30 45 60 90 Example 3(%) 40 62 73 79 84 89 91 95 Example 8(%) 55 73 81 86 90 93 95 96

(118) The results show that the tablets of Example 8 dissolve faster than that of Example 3, indicating that sodium dodecylsulfate comprised in prescription can promote the dissolution of hyzetimibe.

Test Example 9

(119) Study on the Crystal Form of Hyzetimibe

(120) The hyzetimibe placebo and hyzetimibe bulk drug (crystal form I) were mixed at a weight ratio of 98:2. The resulting mixture was subjected to X-ray diffraction (XRD) test to obtain a XRD pattern of the mixture of hyzetimibe placebo and hyzetimibe bulk drug (crystal form I) (see FIG. 3). Then, the XRD pattern of FIG. 3 was compared with that of the hyzetimibe placebo (see FIG. 1) and that of the hyzetimibe bulk drug (crystal form I) (see FIG. 2). At the position of 18° in FIG. 3, a characteristic peak of hyzetimibe crystal form I was detected, and the detection limit of the XRD detection equipment for hyzetimibe crystal form I was judged as 2%, indicating that when the crystal form I in tablets accounts for equal to or more than 2% of the total tablet weight, the crystal form I would be detected. Hyzetimibe tablets with an API content of 20% prepared in Example 11 were subjected to XRD detection, and no peak at 18° was found (see FIG. 4), indicating that in the tablets prepared according to the method of Example 11, the bulk drug present in crystal form I was less than 2% of the tablet weight, that is, in the tablets of Example 11, more than 18% by tablet weight of bulk drug was present in an amorphous form. Therefore, it can be determined that in the tablets of Example 11, hyzetimibe in an amorphous form accounts for more than 90% of the total amount of the bulk drug. Stability of the tablets of Example 11 (hyzetimibe 20 mg, alcohol granulation) was investigated under accelerated conditions (temperature 40±2° C., humidity (RH) 75%±5%), and the results are shown in FIG. 5 and FIG. 6:

(121) FIG. 5 shows that the content of amorphous hyzetimibe is still above 90% under accelerated conditions for 3 months.

(122) FIG. 6 shows that the content of amorphous hyzetimibe is still above 90% under accelerated conditions for 9 months.