JAK KINASE INHIBITOR PHARMACEUTICAL COMPOSITION

Abstract

A JAK kinase inhibitor 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]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof and a co-processed excipient, such as cellulose-lactose. The present invention has good stability, dissolution and bioavailability, and the preparation process thereof is simple and convenient.

Claims

1. A pharmaceutical composition, comprising an active ingredient (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]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof and a filler, wherein the filler is selected from the group consisting of a co-processed excipient, and the co-processed excipient is preferably microcrystalline cellulose-lactose, cellulose-lactose or corn starch-lactose, and more preferably microcrystalline cellulose-lactose or cellulose-lactose.

2. The pharmaceutical composition according to claim 1, wherein the filler, based on the total weight of the pharmaceutical composition, has a content of 40%-95%, preferably 60%-92%.

3. The pharmaceutical composition according to claim 1, further comprising a disintegrant, wherein the disintegrant, based on the total weight of the pharmaceutical composition, has a content of 1%-30%, preferably 2%-20%.

4. The pharmaceutical composition according to claim 3, wherein the disintegrant is free of a metal element, and is preferably at least one of pre-gelatinized starch, adipic acid, alginic acid, gelatinized starch, crospolyvinylpyrrolidone and low-substituted hydroxypropylcellulose.

5. The pharmaceutical composition according to claim 1, further comprising at least one of a glidant and a lubricant, wherein the glidant or the lubricant, based on the total weight of the pharmaceutical composition, has a content of 0.5%-5%, preferably 1%-5%.

6. The pharmaceutical composition according to claim 5, wherein the glidant is free of a metal element, and is preferably at least one of silicon dioxide, light anhydrous silicic acid, crystalline cellulose, stearic acid and corn starch, and more preferably silicon dioxide; and the lubricant is free of a metal element, and is preferably at least one of stearic acid, glyceryl behenate, hydrogenated vegetable oil and silicon dioxide.

7. The pharmaceutical composition according to claim 1, being free of a metal element, wherein the metal element is preferably an alkali metal or an alkaline earth metal.

8. The pharmaceutical composition according to claim 1, wherein the filler further comprises lactose.

9. The pharmaceutical composition according to claim 8, wherein the co-processed excipient and lactose are in a weight ratio of 1:2-5:1, preferably 1:2-2:1.

10. The pharmaceutical composition according to claim 1, comprising the following ingredients based on the total weight of the pharmaceutical composition: 1) 0.1%-30% (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]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, 2) 40%-95% filler, wherein the co-processed excipient and the lactose are in a weight ratio of 1:2-5:1, 3) optionally 1%-30% disintegrant, 4) optionally 0.5%-5% glidant, and 5) optionally 0.5%-5% lubricant, wherein further, the pharmaceutical composition is preferably free of a metal element.

11. A pharmaceutical composition comprising (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]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is free of an excipient containing a metal element.

12. The pharmaceutical composition according to claim 11, further comprising a filler, wherein the filler is preferably at least one of lactose, microcrystalline cellulose-lactose, cellulose-lactose and corn starch-lactose.

13. The pharmaceutical composition according to claim 12, further comprising at least one of a disintegrant, a glidant and a lubricant.

14. The pharmaceutical composition according to claim 11, comprising the following ingredients based on the total weight of the pharmaceutical composition: 1) 0.1%-30% (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]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, 2) 40%-95% filler, wherein the filler is preferably at least one of lactose, microcrystalline cellulose-lactose, cellulose-lactose and corn starch-lactose, 3) optionally 1%-30% disintegrant, 4) optionally 0.5%-5% glidant, and 5) optionally 0.5%-5% lubricant, wherein further, the pharmaceutical composition is preferably free of an excipient containing a metal element.

15. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of the active ingredient is selected from the group consisting of a hydrogen sulphate.

16. The pharmaceutical composition according to claim 1, wherein after the pharmaceutical composition is stored under high humidity conditions for 30 days, the dissolution of the active ingredient is more than 85% at 15 minutes, preferably more than 90% at 30 minutes, when tested in a dissolution test at a paddle speed of 50 rpm at 37±0.5° C. using a phosphate solution at pH 6.8 as a dissolution medium.

17. A method for preparing the pharmaceutical composition according to claim 1, comprising: a) mixing (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]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof with a filler and optionally at least one excipient from a disintegrant and a lubricant; b) granulating the mixture obtained from a), followed by tableting or direct tableting.

18. Use of the pharmaceutical composition according to claim 1 in preparing a medicament for treating a JAK kinase-associated disease, preferably rheumatic and rheumatoid arthritis.

Description

DETAILED DESCRIPTION

[0065] The disclosure is further illustrated 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 disclosure. Experimental procedures without specific conditions indicated in the examples of the disclosure are generally conducted according to conventional conditions favorable to production or according to conditions recommended by the manufacturers of the raw materials or commercial products. Reagents without specific sources indicated are conventional reagents purchased from the market.

[0066] In the following examples, compound A was used to indicate a hydrosulfate salt of (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]pyrrole-2(1H)-carboxamide.

Example 1

[0067] According to the formula proportions of Table 1, compound A, lactose, microcrystalline cellulose and croscarmellose sodium were mixed well, and the mixture was subjected to wet granulation using a 3% hydroxypropyl methylcellulose (HPMC E5) aqueous solution as a wetting agent, followed by tableting to obtain a tablet.

TABLE-US-00001 TABLE 1 Ingredient Formula 1/mg Compound A 1.24 Lactose 70.56 Microcrystalline 22.00 cellulose Croscarmellose 4.00 sodium HPMC E5 1.20 Purified water 38.00 Magnesium stearate 1.00 Total 100.00

[0068] The tablet prepared according to above formula was stored under conditions of 25° C. and RH 90% for 30 days, and determined for the dissolution according to the Dissolution Test Method 2 (paddle method) of Appendix, Chinese Pharmacopoeia, Volume II, 2010 Edition or according to the Method 2 (paddle method) of General Chapter 0931, Chinese Pharmacopoeia, Volume IV, 2015 Edition.

[0069] Dissolution test conditions: tested at a paddle speed of 50 rpm at 37±0.5° C. using 500 mL of a 0.1 mol/L hydrochloric acid solution as a dissolution medium. The specific data for dissolution are shown in Table 2.

TABLE-US-00002 TABLE 2 Time Day 0 Day 30 (min) Dissolution (%) 30 98.5 93.9

[0070] Dissolution test conditions: tested at a paddle speed of 50 rpm at 37±0.5° C. using 500 mL of a hydrochloric acid buffer at pH 6.8 as a dissolution medium. The specific data for dissolution are shown in Table 3.

TABLE-US-00003 TABLE 3 Time Day 0 Day 30 (min) Dissolution (%) 30 94.7 9.7

[0071] Conclusion: 1) the dissolution of the tablet prepared according to the formula 1 at 30 minutes varies in different dissolution media, suggesting that the 0.1 mol/L hydrochloric acid medium cannot truly reflect the changes in the dissolution of the sample, while the phosphate medium at pH 6.8 can reflect the real dissolution of the sample;

[0072] 2) after being stored under high humidity conditions for 30 days, the dissolution of the tablet in the phosphate medium at pH 6.8 is significantly slowed down and the dissolution is incomplete, although the related substances of the sample are not changed, therefore, the formulation product has quality risk in the marketing.

Example 2

[0073] According to the formula proportions of Table 4, compound A, lactose, microcrystalline cellulose and low-substituted hydroxypropylcellulose were mixed well, and the mixture was subjected to wet granulation using a 3% hydroxypropyl methylcellulose aqueous solution as a wetting agent, followed by tableting to obtain a tablet.

TABLE-US-00004 TABLE 4 Ingredient Formula 2/mg Compound A 1.24 Lactose 70.56 Microcrystalline 22.00 cellulose Low-substituted 8.00 hydroxypropylcellulose HPMC E5 1.20 Purified water 38.80 Magnesium stearate 1.00 Total 100

[0074] Dissolution Test

[0075] The tablet prepared according to above formula was stored under conditions of 25° C. and RH 90% for 30 days, and determined for the dissolution according to the Method 2 (paddle method) of General Chapter 0931, Chinese Pharmacopoeia, Volume IV, 2015 Edition. Dissolution test conditions: tested at a paddle speed of 50 rpm at 37±0.5° C. using 500 mL of a hydrochloric acid buffer at pH 6.8 as a dissolution medium. The specific data for dissolution are shown in Table 5.

TABLE-US-00005 TABLE 5 Time Day 0 Day 30 (min) Dissolution (%) 30 95.7 45.4

[0076] Conclusion: 1) the dissolution of the tablets prepared by the formula 1 and formula 2 is rapid and complete initially, and after being stored for a period of time under high humidity conditions, the disintegration rate of the tablets is reduced to different degrees, which leads to a decrease in the dissolution rate and incomplete dissolution;

[0077] 2) compared with the formula 1, the formulation formula including the nonmetallic disintegrant and low-substituted hydroxypropylcellulose, can improve the solubility of the pharmaceutical composition, particularly the dissolution of a sample after being stored at a high temperature for a period of time, and it is speculated that the metal ions will complex with the active ingredient, which affects the disintegration rate of the pharmaceutical composition, so that the dissolution of the pharmaceutical composition after being stored at the high temperature is affected.

Example 3

[0078] According to the proportions of Table 6, compound A, lactose, cellulose-lactose C80 and silicon dioxide were mixed well, followed by the addition of stearic acid, and then the mixture was mixed well. The resulting material was subjected to direct tableting to obtain the desired tablet.

TABLE-US-00006 TABLE 6 Ingredient Formula 3/mg Compound A 4.95 Lactose 109.05 Cellulose-lactose C80 80.00 Silicon dioxide 2.00 Stearic acid 4.00 Total 200

[0079] Dissolution Test

[0080] The tablet prepared according to above formula was stored under conditions of 25° C. and RH 90% for 30 days, and determined for the dissolution according to the Method 2 (paddle method) of General Chapter 0931, Chinese Pharmacopoeia, Volume IV, 2015 Edition.

[0081] Dissolution test conditions: tested at a paddle speed of 50 rpm at 37±0.5° C. using 1000 mL of a hydrochloric acid buffer at pH 6.8 as a dissolution medium. The specific data for dissolution are shown in Table 7.

TABLE-US-00007 TABLE 7 Time Day 0 Day 30 (min) Dissolution (%) 30 99.0 86.8

[0082] Conclusion: after being stored under high humidity conditions, the dissolution of the tablet prepared according to the formula 3 at 30 minutes is reduced, but can still reach above 85% as compared to that of the tablet prepared according to the formula 2, therefore, the product quality requirement is met.

Example 4

[0083] According to the proportions of Table 8, compound A, lactose, cellulose-lactose C80 and colloidal silicon dioxide were mixed well, followed by the addition of stearic acid, and then the mixture was mixed well. The resulting material was subjected to direct tableting to obtain the desired tablet.

TABLE-US-00008 TABLE 8 Ingredient Formula 4/mg Compound A 0.618 Lactose 50.182 Cellulose-lactose C80 40.00 Low-substituted 5.00 hydroxypropylcellulose Silicon dioxide 1.30 Stearic acid 2.00 Total 100

[0084] Dissolution Test

[0085] The tablet prepared according to above formula was stored under conditions of 25° C. and RH 90% for 30 days, and determined for the dissolution according to the Method 2 (paddle method) of General Chapter 0931, Chinese Pharmacopoeia, Volume IV, 2015 Edition.

[0086] Dissolution test conditions: tested at a paddle speed of 50 rpm at 37±0.5° C. using 500 mL of a hydrochloric acid buffer at pH 6.8 as a dissolution medium. The specific data for dissolution are shown in Table 9.

TABLE-US-00009 TABLE 9 Time Day 0 Day 30 (min) Dissolution (%) 5 96 79 10 100 91 15 101 96 30 101 101

[0087] It can be seen that the above sample maintains excellent dissolution after being stored under high humidity conditions for a period of time, such as 30 days, and it is expected that the formulation product meets the requirement of controllable quality risk for the product after marketing.

Example 5

[0088] According to the proportions of Table 10, compound A, lactose, cellulose-lactose C80, low-substituted hydroxypropylcellulose, colloidal silicon dioxide and stearic acid were mixed well. The resulting material was subjected to direct tableting to obtain the desired tablet. The tablet was coated with a film coating premix (gastric soluble), and packaged with pharmaceutical aluminum foil.

TABLE-US-00010 TABLE 10 Ingredient Formula/mg Compound A 9.89 Lactose 196.91 Cellulose-lactose C80 160.00 Low-substituted 20.00 hydroxypropylcellulose Silicon dioxide 5.20 Stearic acid 8.00

[0089] The above sample was stored under conditions of 30±2° C., RH 65% 5% (long-term) and 40±2° C., RH 75%±5% (accelerated) to investigate the stability and dissolution of the sample.

[0090] Dissolution test conditions: tested at a paddle speed of 50 rpm at 37±0.5° C. using 500 mL of a hydrochloric acid buffer at pH 6.8 as a dissolution medium.

TABLE-US-00011 TABLE 11 Long-term Accelerated Time Content Dissolution Content Dissolution (month) (%) (%).sup.b (%) (%).sup.b 0 98.3 94-97 98.3 94-97 1 / / 98.7  97-101 2 / / 98.2 95-98 3 97.5 95-98 97.7 95-97 6 97.2 96-99 97.4 97-99 9 97.6 95-98 / / 12 96.2 95-97 / / Note: .sup.acalibrating the content of the sample by HPLC; .sup.bdissolution after 30 minutes.