Pharmaceutical formulations containing an SGLT2 inhibitor
View Patent ↗Pharmaceutical formulations are provided which are in the form of capsules or tablets for oral use and which include a medicament dapagliflozin or its propylene glycol hydrate and a pharmaceutical acceptable carrier therefor, which formulation is designed for immediate release.
1. An immediate release pharmaceutical formulation comprising a dapagliflozin propylene glycol hydrate selected from the (S)-propylene glycol hydrate having the formula
and the (R)-propylene glycol hydrate having the formula
and a pharmaceutically acceptable carrier, in a form selected from the group consisting of a tablet, a stock granulation, and a capsule, wherein the dapagliflozin propylene glycol hydrate is present in an amount to provide a daily dose within the range of from about 0.1 to about 750 mg per day in single or divided doses or multiple doses, which is administered 1 to 4 times, wherein
the dapagliflozin propylene glycol hydrate is present in an amount within the range of from 0.1% to 70% of tablet or capsule fill; and
the pharmaceutically acceptable carrier comprises:
one or more bulking agents/binders in an amount within the range of from 1% to 95% by weight of tablet or capsule fill, the one or more bulking agents/binders comprising one or more of anhydrous lactose in an amount within the range of 0% to 95% by weight of tablet or capsule fill, microcrystalline cellulose in an amount within the range of 0% to 95% by weight of tablet or capsule fill, and pregelatinized starch in an amount within the range of 0 to 95% by weight of tablet or capsule fill;
one or more disintegrants in an amount within the range of from 0% to 20% by weight of tablet or capsule fill, the one or more disintegrants comprising one or more of croscarmellose sodium in an amount within the range of 0% to 20% by weight of tablet or capsule fill, crospovidone in an amount within the range of 0% to 12% by weight of tablet or capsule fill, and sodium starch glycolate in an amount within the range of 0% to 20% by weight of tablet or capsule fill;
one or more glidants and/or anti-adherents comprising one or more of talc and silicon dioxide in an amount within the range from 0% to 10% by weight of tablet or capsule fill; and
one or more lubricants comprising magnesium stearate in an amount within the range of 0.1% to 5% by weight of tablet or capsule fill.
2. The pharmaceutical formulation according to claim 1 , wherein the dapagliflozin propylene glycol hydrate is the (R)-propylene glycol hydrate having the formula
3. The formulation according to claim 1 in the form of a stock granulation for loading in capsules or forming tablets.
4. The formulation according to claim 1 , in capsule form.
5. The formulation according to claim 1 , in tablet form.
6. The formulation according to claim 1 comprising:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount within the range of from about 0.1% to about 30% by weight of tablet or capsule fill;
b) bulking agents in a total amount within the range of from about 10% to about 85% by weight of tablet or capsule fill comprising one or more of lactose present in an amount within the range of from about 20% to about 75% by weight of tablet or capsule fill, and microcrystalline cellulose present in an amount within the range of from about 20% to about 75% by weight of tablet or capsule fill;
c) a binder comprising pregelatinized starch present in an amount within the range of from about 10% to about 75% by weight of tablet or capsule fill;
d) disintegrants in a total amount within the range of from about 2% to about 10% by weight of tablet or capsule fill, comprising one or more of croscarmellose sodium present in an amount within the range of from about 2% to about 10% by weight of tablet or capsule fill, crospovidone present in an amount within the range of from about 4% to about 10% by weight of tablet or capsule fill, and sodium starch glycolate present in an amount within the range of from about 2% to about 10% by weight of tablet or capsule fill;
e) one or more glidants and/or anti-adherents comprising talc and/or silicon dioxide, wherein the total amount of glidant and/or anti-adherent is present in an amount within the range of from about 1% to about 10% by weight of tablet or capsule fill;
f) a lubricant comprising magnesium stearate present in an amount within the range of from about 0.2% to about 2% by weight of tablet or capsule fill; and
g) optionally further comprising an outer protective coating layer comprising a coating polymer and optionally comprising one or more of the following: a plasticizer(s), anti-tacking agent(s), glidant(s), and colorant(s), wherein the total amount of the outer protective coating layer is present in an amount within the range of from about 1% to about 5% by weight of tablet or capsule fill.
7. The formulation according to claim 6 , wherein the dapagliflozin propylene glycol hydrate is the (S)-propylene glycol hydrate having the formula
8. The formulation according to claim 1 in the form of a capsule filled with a stock granulation comprising:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount of 10% by weight of capsule fill;
b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount of 68.75% by weight of capsule fill;
c) pregelatinized starch, wherein the pregelatinized starch is present in an amount of 15% by weight of capsule fill;
d) sodium starch glycolate, wherein the sodium starch glycolate is present in an amount of 3% by weight of capsule fill;
e) silicon dioxide, wherein the silicon dioxide is present in an amount of 2% by weight of capsule fill; and
f) magnesium stearate, wherein the magnesium stearate is present in an amount of 1.25% by weight of capsule fill.
9. The formulation according to claim 8 , wherein the dapagliflozin propylene glycol hydrate is the (S)-propylene glycol hydrate having the formula
10. The formulation according to claim 1 in the form of a capsule filled with a stock granulation comprising:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount of 22.8% by weight of capsule fill;
b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount of 55.95% by weight of capsule fill;
c) pregelatinized starch, wherein the pregelatinized starch is present in an amount of 15% by weight of capsule fill;
d) sodium starch glycolate, wherein the sodium starch glycolate is present in an amount of 3% by weight of capsule fill;
e) silicon dioxide, wherein the silicon dioxide is present in an amount of 2% by weight of capsule fill; and
f) magnesium stearate, wherein the magnesium stearate is present in an amount of 1.25% by weight of capsule fill.
11. The formulation according to claim 10 , wherein the dapagliflozin propylene glycol hydrate is the (S)-propylene glycol hydrate having the formula
12. The formulation according to claim 1 in the form of a 2.5 mg dapagliflozin dose tablet comprising:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount of 3.08 mg;
b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount of 67.11 mg;
c) anhydrous lactose, wherein the anhydrous lactose is present in an amount of 25 mg;
d) crospovidone, wherein the crospovidone is present in an amount of 8.75 mg;
e) croscarmellose sodium, wherein the croscarmellose sodium is present in an amount of 3.75 mg;
f) talc, wherein the talc is present in an amount of 12.5 mg;
g) silicon dioxide, wherein the silicon dioxide is present in an amount of 2.88 mg; and
h) magnesium stearate, wherein the magnesium stearate is present in an amount of 1.94 mg.
13. The formulation according to claim 12 , wherein the dapagliflozin propylene glycol hydrate is the (S)-propylene glycol hydrate having the formula
14. The formulation according to claim 1 in the form of a 10 mg dapagliflozin dose tablet comprising:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount of 12.3 mg;
b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount of 57.89 mg;
c) anhydrous lactose, wherein the anhydrous lactose is present in an amount of 25 mg;
d) crospovidone, wherein the crospovidone is present in an amount of 8.75 mg;
e) croscarmellose sodium, wherein the croscarmellose sodium is present in an amount of 3.75 mg;
f) talc, wherein the talc is present in an amount of 12.5 mg;
g) silicon dioxide, wherein the silicon dioxide is present in an amount of 2.88 mg; and
h) magnesium stearate, wherein the magnesium stearate is present in an amount of 1.94 mg.
15. The formulation according to claim 14 , wherein the dapagliflozin propylene glycol hydrate is the (S)-propylene glycol hydrate having the formula
16. The formulation according to claim 1 in the form of a 50 mg dapagliflozin dose tablet comprising:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount of 61.66 mg;
b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount of 114.09 mg;
c) anhydrous lactose, wherein the anhydrous lactose is present in an amount of 62.6 mg;
d) crospovidone, wherein the crospovidone is present in an amount of 21.91 mg;
e) croscarmellose sodium, wherein the croscarmellose sodium is present in an amount of 9.39 mg;
f) talc, wherein the talc is present in an amount of 31.3 mg;
g) silicon dioxide, wherein the silicon dioxide is present in an amount of 7.2 mg; and
h) magnesium stearate, wherein the magnesium stearate is present in an amount of 4.85 mg.
17. The formulation according to claim 16 , wherein the dapagliflozin propylene glycol hydrate is the (S)-propylene glycol hydrate having the formula
18. The formulation according to claim 1 , wherein
the dapagliflozin propylene glycol hydrate is present in an amount within the range of from about 0.1% to about 30% of the stock granulation;
the one or more bulking agents are selected from microcrystalline cellulose and anhydrous lactose, present in an amount within the range of from about 10% to about 85% by weight of the stock granulation;
a separate binder is not present;
the disintegrant is selected from crospovidone and croscarmellose sodium present in an amount within the range of from about 0.25% to about 10% by weight of the stock granulation;
the glidant and/or anti-adherent is selected from talc and silicon dioxide present in an amount within the range from about 1% to about 15% by weight of the stock granulation; and
the lubricant is magnesium stearate present in an amount within the range from about 0.2% to about 2% by weight of the stock granulation.
19. The formulation according to claim 18 , wherein the dapagliflozin propylene glycol hydrate is the (S)-propylene glycol hydrate having the formula
20. The formulation as defined in claim 1 in the form of a tablet or capsule, wherein
the dapagliflozin propylene glycol hydrate is present in an amount within the range of from 0.1% to 30% of tablet or capsule fill; and
the pharmaceutically acceptable carrier comprises:
one or more bulking agents/binders in an amount within the range of from 10 to 85% by weight of tablet or capsule fill, the one or more bulking agents/binders comprising one or more of anhydrous lactose in an amount within the range of 20 to 75% by weight of tablet or capsule fill, microcrystalline cellulose in an amount within the range of 20 to 75% by weight of tablet or capsule fill, and pregelatinized starch in an amount within the range of 10 to 75% by weight of tablet or capsule fill;
one or more disintegrants in an amount within the range of from 0.25 to 10% by weight of tablet or capsule fill, the one or more disintegrants comprising one or more of croscarmellose sodium in an amount within the range of 2 to 10% by weight of tablet or capsule fill, crospovidone in an amount within the range of 4 to 10% by weight of tablet or capsule fill, and sodium starch glycolate in an amount within the range of 2 to 10% by weight of tablet or capsule fill;
one or more glidants and/or anti-adherents comprising one or more of talc and silicon dioxide in an amount within the range from 1 to 4% by weight of tablet or capsule fill; and
one or more lubricants comprising magnesium stearate in an amount within the range of 0.2 to 2% by weight of tablet or capsule fill.
21. The formulation according to claim 20 , wherein the dapagliflozin propylene glycol hydrate is the (S)-propylene glycol hydrate having the formula
22. The formulation according to claim 20 in the form of a tablet or capsule, wherein
the dapagliflozin propylene glycol hydrate is present in an amount within the range of from 0.1% to 30% of tablet or capsule fill;
the one or more bulking agents/binders are anhydrous lactose in an amount within the range of 20% to 75% by weight of tablet or capsule fill, and microcrystalline cellulose in an amount within the range of 20% to 75% by weight of tablet or capsule fill;
the one or more disintegrants are croscarmellose sodium in an amount within the range of 2% to 10% by weight of tablet or capsule fill, and crospovidone in an amount within the range of 4% to 10% by weight of tablet or capsule fill;
the one or more glidants and/or anti-adherents are talc and silicon dioxide in an amount within the range from 1% to 10% by weight of tablet or capsule fill; and
the one or more lubricants are magnesium stearate in an amount within the range of 0.2% to 2% by weight of tablet or capsule fill.
23. The formulation according to claim 22 , wherein the dapagliflozin propylene glycol hydrate is the (S)-propylene glycol hydrate having the formula
24. The formulation according to claim 1 , wherein the formulation comprises:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount within the range of from about 0.1% to about 15% by weight of tablet or capsule fill;
b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount sufficient to make the total weight of the tablet or capsule fill 100%;
c) lactose, wherein the lactose is present in an amount within the range of from about 10% to about 30% by weight of tablet or capsule fill;
d) crospovidone, wherein the crospovidone is present in an amount within the range of from about 3% to about 10% by weight of tablet or capsule fill;
e) silicon dioxide, wherein the silicon dioxide is present in an amount within the range of from about 0.5% to about 4% by weight of tablet or capsule fill; and
f) magnesium stearate, wherein the magnesium stearate is present in an amount within the range of from about 0.5% to about 2% by weight of tablet or capsule fill.
25. The formulation according to claim 24 , wherein the dapagliflozin propylene glycol hydrate is the (S)-propylene glycol hydrate having the formula
26. The formulation according to claim 1 , wherein said formulation is in the form of a 1.0 mg dapagliflozin dose tablet comprising:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount of 1.23 mg;
b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount of about 50 mg to about 90 mg;
c) lactose, wherein the lactose is present in an amount of about 10 mg to about 30 mg;
d) crospovidone, wherein the crospovidone is present in an amount of about 2 mg to about 10 mg;
e) silicon dioxide, wherein the silicon dioxide is present in an amount of about 0.5 mg to about 4.0 mg;
f) magnesium stearate, wherein the magnesium stearate is present in an amount of about 0.5 mg to about 2.0 mg; and
g) an antioxidant and/or chelating agent, wherein the antioxidant and/or chelating agent is present in an amount of about 0 mg to about 0.5 mg.
27. The formulation according to claim 26 , wherein the dapagliflozin propylene glycol hydrate is the (S)-propylene glycol hydrate having the formula
28. The formulation according to claim 1 , wherein said formulation is in the form of a 2.5 mg dapagliflozin dose tablet comprising:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount of 3.075 mg;
b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount of about 60 mg to about 115 mg;
c) lactose, wherein the lactose is present in an amount of about 12.5 mg to about 38 mg;
d) crospovidone, wherein the crospovidone is present in an amount of about 2.5 mg to about 13 mg;
e) silicon dioxide, wherein the silicon dioxide is present in an amount of about 0.6 mg to about 5.0 mg;
f) magnesium stearate, wherein the magnesium stearate is present in an amount of about 0.6 mg to about 2.5 mg; and
g) an antioxidant and/or chelating agent, wherein the antioxidant and/or chelating agent is present in an amount of about 0 mg to about 0.6 mg.
29. The formulation according to claim 28 , wherein the dapagliflozin propylene glycol hydrate is the (S)-propylene glycol hydrate having the formula
30. The formulation according to claim 1 , wherein said formulation is in the form of a 5.0 mg dapagliflozin dose tablet comprising:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount of 6.15 mg;
b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount of about 60 mg to about 115 mg;
c) lactose, wherein the lactose is present in an amount of about 12.5 mg to about 38 mg;
d) crospovidone, wherein the crospovidone is present in an amount of about 2.5 mg to about 13 mg;
e) silicon dioxide, wherein the silicon dioxide is present in an amount of about 0.6 mg to about 5.0 mg;
f) magnesium stearate, wherein the magnesium stearate is present in an amount of about 0.6 mg to about 2.5 mg; and
g) an antioxidant and/or chelating agent, wherein the antioxidant and/or chelating agent is present in an amount of about 0 mg to about 0.6 mg.
31. The formulation according to claim 30 , wherein the dapagliflozin propylene glycol hydrate is the (S)-propylene glycol hydrate having the formula
32. The formulation according to claim 1 , wherein said formulation is in the form of a 10 mg dapagliflozin dose tablet comprising:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount of 12.3 mg;
b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount of about 120 mg to about 230 mg;
c) lactose, wherein the lactose is present in an amount of about 25 mg to about 75 mg;
d) crospovidone, wherein the crospovidone is present in an amount of about 5 mg to about 25 mg;
e) silicon dioxide, wherein the silicon dioxide is present in an amount of about 1.0 mg to about 10 mg;
f) magnesium stearate, wherein the magnesium stearate is present in an amount of about 1.0 mg to about 5 mg; and
g) an antioxidant and/or chelating agent, wherein the antioxidant and/or chelating agent is present in an amount of about 0 mg to about 1.25 mg.
33. The formulation according to claim 32 , wherein the dapagliflozin propylene glycol hydrate is the (S)-propylene glycol hydrate having the formula
34. The formulation according to claim 1 , comprising:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount within the range of from about 0.1% to about 15% by weight of tablet or capsule fill;
b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount sufficient to make the total weight of the tablet or capsule fill 100%;
c) lactose, wherein the lactose is present in an amount within the range of from about 10% to about 30% by weight of tablet or capsule fill;
d) crospovidone, wherein the crospovidone is present in an amount within the range of from about 3% to about 10% by weight of tablet or capsule fill;
e) silicon dioxide, wherein the silicon dioxide is present in an amount within the range of from about 0.5% to about 4% by weight of tablet or capsule fill; and
f) magnesium stearate, wherein the magnesium stearate is present in an amount within the range of from about 0.5% to about 2% by weight of tablet or capsule fill.
35. The formulation according to claim 1 , in the form of a 1.0 mg tablet comprising:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount of 1.23 mg;
b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount of about 50 mg to about 90 mg;
c) lactose, wherein the lactose is present in an amount of about 10 mg to about 30 mg;
d) crospovidone, wherein the crospovidone is present in an amount of about 2 mg to about 10 mg;
e) silicon dioxide, wherein the silicon dioxide is present in an amount of about 0.5 mg to about 4.0 mg;
f) magnesium stearate, wherein the magnesium stearate is present in an amount of about 0.5 mg to about 2.0 mg; and
g) an antioxidant and/or chelating agent, wherein the antioxidant and/or chelating agent is present in an amount of about 0 mg to about 0.5 mg.
36. The formulation according to claim 1 , in the form of a 2.5 mg tablet comprising:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount of 3.075 mg;
b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount of about 60 mg to about 115 mg;
c) lactose, wherein the lactose is present in an amount of about 12.5 mg to about 38 mg;
d) crospovidone, wherein the crospovidone is present in an amount of about 2.5 mg to about 13 mg;
e) silicon dioxide, wherein the silicon dioxide is present in an amount of about 0.6 mg to about 5.0 mg;
f) magnesium stearate, wherein the magnesium stearate is present in an amount of about 0.6 mg to about 2.5 mg; and
g) an antioxidant and/or chelating agent, wherein the antioxidant and/or chelating agent is present in an amount of about 0 mg to about 0.6 mg.
37. The formulation according to claim 1 , in the form of a 5.0 mg tablet comprising:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount of 6.15 mg;
b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount of about 60 mg to about 115 mg;
c) lactose, wherein the lactose is present in an amount of about 12.5 mg to about 38 mg;
d) crospovidone, wherein the crospovidone is present in an amount of about 2.5 mg to about 13 mg;
e) silicon dioxide, wherein the silicon dioxide is present in an amount of about 0.6 mg to about 5.0 mg;
f) magnesium stearate, wherein the magnesium stearate is present in an amount of about 0.6 mg to about 2.5 mg; and
g) an antioxidant and/or chelating agent, wherein the antioxidant and/or chelating agent is present in an amount of about 0 mg to about 0.6 mg.
38. The formulation according to claim 1 , in the form of a 10 mg tablet comprising:
a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount of 12.3 mg;
b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount of about 120 mg to about 230 mg;
c) lactose, wherein the lactose is present in an amount of about 25 mg to about 75 mg;
d) crospovidone, wherein the crospovidone is present in an amount of about 5 mg to about 25 mg;
e) silicon dioxide, wherein the silicon dioxide is present in an amount of about 1.0 mg to about 10 mg;
f) magnesium stearate, wherein the magnesium stearate is present in an amount of about 1.0 mg to about 5 mg; and
g) an antioxidant and/or chelating agent, wherein the antioxidant and/or chelating agent is present in an amount of about 0 mg to about 1.25 mg.