Pharmaceutical composition containing JAK kinase inhibitor or pharmaceutically acceptable salt thereof

Abstract

Provided in the present invention is a pharmaceutical composition containing a JAK kinase inhibitor or a pharmaceutically acceptable salt thereof. In particular, provided in the present invention is a pharmaceutical composition containing (3aR, 5s, 6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) hexahydrocyclopenta [c] pyrrol-2 (1H)-carboxamide, or a pharmaceutically acceptable salt thereof, and cellulose ether. The pharmaceutical composition of the present invention is characterized by a rapid dissolution rate and good stability.

Claims

1. A pharmaceutical composition, comprising (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, and hydroxypropyl methyl cellulose in an amount of 1-10% by weight, relative to the total weight of the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, further comprising a filler, wherein the filler comprises one or more selected from the group consisting of lactose, microcrystalline cellulose, mannitol, and pregelatinized starch.

3. The pharmaceutical composition according to claim 1, further comprising a disintegrant, wherein the disintegrant comprises one or more selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch and crospovidone.

4. The pharmaceutical composition according to claim 1, further comprising a lubricant, wherein the lubricant comprises one or more selected from the group consisting of talc, magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, and colloidal silicon dioxide.

5. A pharmaceutical composition, comprising: 1) 0.1%-30% by weight of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof; 2) 1-10% by weight of hydroxypropyl methyl cellulose; 3) 40%-95% by weight of a filler, wherein the filler comprises lactose and microcrystalline cellulose; 4) 1%-20% by weight of a disintegrant, wherein the disintegrant is one or both of croscarmellose sodium and carboxymethyl starch sodium; and 5) optionally 0.5%-5% by weight of magnesium stearate.

6. A method for preparing the pharmaceutical composition according to claim 1, comprising mixing (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof with the hydroxypropyl methyl cellulose to obtain a mixture, and granulating the mixture.

7. A method for treating a disease associated with JAK kinase in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 1.

8. The method according to claim 7, wherein the disease is selected from the group consisting of rheumatic and rheumatoid arthritis.

9. A method for treating a disease associate with JAK kinase in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 5.

10. The method according to claim 9, wherein the disease is selected from the group consisting of rheumatic and rheumatoid arthritis.

11. The pharmaceutical composition according to claim 1, wherein the hydroxypropyl methyl cellulose is present in an amount 1.5-5% by weight, relative to the total weight of the pharmaceutical composition.

12. The pharmaceutical composition according to claim 1, wherein the hydroxypropyl methyl cellulose is present in an amount 2-3% by weight, relative to the total weight of the pharmaceutical composition.

Description

DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the dissolution profiles of the tablets of Examples 1 to 6 in a 0.1 mol/L hydrochloric acid solution.

(2) FIG. 2 shows the dissolution profiles of the tablets of Examples 7 to 9 in a 0.1 mol/L hydrochloric acid solution.

(3) FIG. 3 shows the dissolution profiles of the tablets of Examples 10 to 12 in a 0.1 mol/L hydrochloric acid solution.

DETAILED DESCRIPTION OF THE INVENTION

(4) 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.

(5) In the following examples, compound A is used to represent the bisulfate of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2 (1H)-carboxamide.

Examples 1 to 6

(6) Compound A, mannitol, lactose, microcrystalline cellulose, pregelatinized starch, and croscarmellose sodium were mixed well according to the ratio shown in Table 1. Wet granulation was carried out using a 4% aqueous solution of hydroxypropyl methyl cellulose E5 as a wetting agent. The granules were compressed into tablets.

(7) TABLE-US-00001 TABLE 1 Exam- Exam- Exam- Exam- Exam- Exam- Ingredients ple 1 ple 2 ple 3 ple 4 ple 5 ple 6 Compound A 0.5 15 35 65 50 50 Mannitol 274.3 274.1 Lactose 56.20 101.1 85.3 256.8 Pregelatinized 77.55 starch Micro- 27.0 50.6 42.6 129.0 137.2 137.0 crystalline cellulose CCNa 3.6 7.2 10.8 30.0 20.0 20.0 HPMC E5 1.8 4.3 4.5 14.2 13.5 13.9 Purified water 43.2 103.2 108.0 340.8 324.0 333.6 Magnesium 0.9 1.8 1.8 5.0 5.0 5.0 stearate Total 90 180 180 500 500 500 Unit: mg

Examples 7 to 9

(8) Compound A, lactose, microcrystalline cellulose, sodium carboxymethyl starch, and crospovidone were mixed well according to the ratio shown in Table 2. Wet granulation was carried out using a 4% aqueous solution of hydroxypropyl methyl cellulose E15 as a wetting agent. The granules were compressed into tablets.

(9) TABLE-US-00002 TABLE 2 Ingredients Example 7 Example 8 Example 9 Compound A 12 20 20 Lactose 104.2 95.4 85.3 Microcrystalline 50.6 47.7 42.6 cellulose CMS-Na 7.2 10.8 PVPP 14.4 HPMC E15 4.2 4.3 4.5 Purified water 100.8 103.2 108.0 Magnesium 1.8 1.8 1.8 stearate Total 180 180 180 Unit: mg

Examples 10 to 12

(10) Compound A, lactose, microcrystalline cellulose, and croscarmellose sodium were mixed well according to the prescription ratio shown in Table 3. Wet granulation was carried out using a 10% aqueous solution of polyvinylpyrrolidone, a 10% aqueous solution of starch, and a 4% aqueous solution of hydroxypropyl methyl cellulose as a wetting agent, respectively. The granules were compressed into tablets of Examples 10 to 12.

(11) TABLE-US-00003 TABLE 3 Ingredients Example 10 Example 11 Example 12 Compound A 20 20 20 Lactose 91.86 92.19 95.9 Microcrystalline 46.0 46.0 48.0 cellulose Croscarmellose 7.2 7.2 7.2 sodium PVP K30 9.54 Starch 9.21 HPMC E5 4.6 Purified water 85.86 82.89 110.4 Magnesium stearate 1.8 1.8 1.8 Total 180 180 180 Unit: mg

Example 13

Preparation of Compound A

(12) 1.0 g (2.4 mmol) of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-carboxamide was added to a 50 ml Erlenmeyer flask, followed by addition of 12 ml of dichloromethane and 3 ml of anhydrous methanol. The mixture was stirred at room temperature, and then 0.25 g (2.5 mmol) of concentrated sulfuric acid was added dropwise. After the suspension became clear, the insoluble substances were removed by filtration. No solid was precipitated after the filtrate was stirred for 6 hours. Then, 10 ml of isopropanol was added, and then a large amount of white solid was precipitated. The mixture was stirred for another 18 hours, filtered and dried to obtain 1.138 g of a white solid in a yield of 92.1%.

Experimental Example 1

Dissolution Test

(13) The dissolution rates of the tablets of Examples 1-12 were determined according to the second method (paddle method) of the dissolution rate test described in the appendix of volume II of Chinese Pharmacopoeia 2010 Edition. The dissolution test was carried out using 1000 ml of 0.1 mol/L hydrochloric acid solution as a dissolution medium at 370.5 C. and at a paddle speed of 50 rpm. The dissolution profiles are shown in FIGS. 1, 2 and 3. The results of dissolution rates are shown in Table 4, 5 and 6.

(14) TABLE-US-00004 TABLE 4 Results of dissolution rates of various formulations in Examples 1-6 Dissolution rate (%) Time Exam- Exam- Exam- Exam- Exam- Exam- (min) ple 1 ple 2 ple 3 ple 4 ple 5 ple 6 5 70.4% 61.7% 60.1% 67.4% 58.6% 62.7% 10 90.1% 85.9% 80.7% 80.4% 79.4% 85.1% 15 93.5% 93.2% 88.4% 90.8% 87.2% 87.9% 30 95.7% 96.4% 93.1% 95.1% 93.1% 94.6% 45 98.2% 98.1% 97.4% 97.3% 97.4% 98.2% 60 99.7% 98.6% 98.8% 98.1% 99.6% 99.5%

(15) In Examples 1-6, the tablets dissolve rapidly and completely; in Examples 4-5, although the content of API is high, the prepared tablets can still dissolve rapidly and completely.

(16) TABLE-US-00005 TABLE 5 Results of dissolution rates of various formulations in Examples 7-9 Dissolution rate (%) Time (min) Example 7 Example 8 Example 9 5 60.7% 65.3% 50.2% 10 83.2% 80.7% 70.4% 15 90.3% 87.4% 83.2% 30 94.9% 97.8% 93.1% 45 97.2% 99.1% 95.9% 60 99.3% 100.1% 97.9%

(17) TABLE-US-00006 TABLE 6 Results of dissolution rates of various formulations in Examples 10-12 Dissolution rate (%) Time (min) Example 10 Example 11 Example 12 5 60.8% 56.9% 50.7% 10 83.4% 78.9% 73.1% 15 89.6% 86.4% 85.3% 30 93.2% 92.6% 92.4% 45 94.9% 96.7% 97.8% 60 98.9% 99.4% 100.1%

(18) The results of Examples 7-12 show that the prepared tablets can dissolve rapidly and completely.

Experimental Example 2

Stability Test

(19) The tablets of Examples 9, 10, 11 and 12 were placed under an open condition at a temperature of 40 C. and relative humidity of 75% for 7 days, and then the degradation products were determined by a HPLC method.

(20) The results of degradation products test show that, with respect to the tablets of Examples 9 and 12 in which hydroxypropyl methyl cellulose was used as the binder, the degradation products did not increase. However, with respect to the tablets of Examples 10 and 11 in which polyvinylpyrrolidone and starch were used as the binder respectively, the degradation products increased obviously (see Table 7).

(21) TABLE-US-00007 TABLE 7 Initial state Placed for 7 days Degradation Content of Degradation Content of products compound products compound (%) A (%) (%) A (%) Example 9 0.82 99.46 0.84 99.56 Example 10 0.84 99.67 1.34 99.73 Example 11 0.79 99.84 1.42 99.89 Example 12 0.86 100.12 0.84 100.01