Formulations of a Bruton's tyrosine kinase inhibitor
Described herein is the Bruton's tyrosine kinase (Btk) inhibitor 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, including novel pharmaceutical formulations thereof. Also disclosed are pharmaceutical compositions that include the Btk inhibitor, as well as methods of using the Btk inhibitor, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.
1. A solid dispersion formulation, wherein the formulation comprises a) about 5% w/w to about 50% w/w of 20% to 80% active spray-dried ibrutinib, wherein ibrutinib is a compound of formula (I),
b) about 10% w/w to about 75% w/w of lactose;
c) about 5% w/w to about 50% w/w of microcrystalline cellulose;
d) about 0% w/w to about 15% w/w of croscarmellose sodium;
e) about 0.25% w/w to about 2.5% w/w of magnesium stearate; and
wherein the 20% to 80% active spray-dried ibrutinib is a spray-dried ibrutinib composition comprising about 20% w/w to about 80% w/w of ibrutinib dispersed into a polymer matrix, wherein the polymer matrix is hypromellose.
2. The solid dispersion formulation of claim 1 , wherein the formulation comprises
lactose in an amount from about 10% w/w to about 20% w/w or about 14% w/w to about 19% w/w;
microcrystalline cellulose in an amount from about 20% w/w to about 30% w/w, about 23% w/w to about 28% w/w, or about 24% w/w to about 26% w/w;
crosscarmellose sodium in an amount from about 3% w/w to about 9% w/w, about 4% w/w to about 8% w/w, or about 5% w/w to about 7% w/w; and
magnesium stearate in an amount from about 0.1% w/w to about 0.5% w/w or about 0.4% w/w to about 0.5% w/w.
3. The solid dispersion formulation of claim 1 , wherein ibrutinib is in an amount of about 300 mg to about 1000 mg.
4. The solid dispersion formulation of claim 1 , wherein ibrutinib is in an amount of about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 700 mg in a capsule.
5. The solid dispersion formulation of claim 1 , wherein the formulation is used for once a day dosing.
6. A solid dispersion formulation, wherein the formulation comprises
a) about 10% w/w to about 25% w/w of 20% to 50% active spray-dried ibrutinib, wherein ibrutinib is a compound of formula (I)
b) about 13% w/w to about 18% w/w of lactose;
c) about 24% w/w to about 26% w/w of microcrystalline cellulose;
d) about 5% w/w to about 7% w/w of croscarmellose sodium;
e) about 0% w/w to about 2% w/w colloidal silicon dioxide;
f) about 0% w/w to about 1% w/w of magnesium stearate;
and wherein the 20% to 50% active spray-dried ibrutinib is a spray-dried ibrutinib composition comprising about 20% w/w to about 50% w/w of ibrutinib dispersed into a polymer matrix, wherein the polymer matrix is hydroxypropyl methyl cellulose acetate succinate (HPMCAS), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOLUPLUS®), or a mixture thereof.
7. The solid dispersion formulation of claim 6 , wherein the excipients comprise
lactose in an amount from about 14% w/w to about 17% w/w;
colloidal silicon dioxide in an amount of about 0%; and
magnesium stearate in an amount of about 0%.
8. The solid dispersion formulation of claim 6 , wherein ibrutinib is in an amount of about 300 mg to about 1000 mg.
9. The solid dispersion formulation of claim 6 , wherein ibrutinib is in an amount of about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 700 mg in a capsule.
10. The solid dispersion formulation of claim 6 , wherein the formulation is used for once a day dosing.
11. A solid dispersion formulation comprising
a) about 5% w/w to about 50% w/w of 20% to 80% active spray-dried ibrutinib, wherein ibrutinib is a compound of formula (I),
b) about 10% w/w to about 75% w/w of lactose;
c) about 5% w/w to about 50% w/w of microcrystalline cellulose;
d) about 0% w/w to about 15% w/w of croscarmellose sodium;
e) about 0.25% w/w to about 2.5% w/w of magnesium stearate; and
wherein the 20% to 80% active spray-dried ibrutinib is a spray-dried ibrutinib composition comprising about 20% w/w to about 80% w/w of ibrutinib dispersed into a polymer matrix, wherein the polymer matrix is hypromellose;
wherein the solid dispersion formulation provides about 2-fold to about 25-fold increase in drug exposure compared to a capsule formulation comprising ibrutinib that is not in a solid dispersed composition.
12. The solid dispersion formulation of claim 11 , wherein the solid dispersion formulation provides about 3-fold to about 20-fold increase in drug exposure compared to a capsule formulation comprising ibrutinib that is not in a solid dispersed composition.
13. The solid dispersion formulation of claim 11 , wherein the solid dispersion formulation provides about 8-fold to about 11-fold increase in drug exposure compared to a capsule formulation comprising ibrutinib that is not in a solid dispersed composition.
14. The solid dispersion formulation of claim 11 , wherein the drug exposure is evaluation based on average area under the curve (AUC) of ibrutinib in a population of healthy human adults in a fasted state.
15. The solid dispersion formulation of claim 14 , wherein the AUC is about 450 ng*h/mL to about 5500 ng*h/mL.
16. The solid dispersion formulation of claim 14 , wherein the AUC is about 1200 ng*h/mL to about 2000 ng*h/mL.
17. The solid dispersion formulation of claim 11 , wherein ibrutinib is in an amount of about 300 mg to about 1000 mg.
18. The solid dispersion formulation of claim 11 , wherein ibrutinib is in an amount of about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 700 mg in a capsule.
19. The solid dispersion formulation of claim 11 , wherein the formulation is used for once a day dosing.
20. A solid dispersion formulation comprising
a) about 5% w/w to about 50% w/w of 20% to 80% active spray-dried ibrutinib, wherein ibrutinib is a compound of formula (I),
b) about 10% w/w to about 75% w/w of lactose;
c) about 5% w/w to about 50% w/w of microcrystalline cellulose;
d) about 0% w/w to about 15% w/w of croscarmellose sodium;
e) about 0.25% w/w to about 2.5% w/w of magnesium stearate; and
wherein the 20% to 80% active spray-dried ibrutinib is a spray-dried ibrutinib composition comprising about 20% w/w to about 80% w/w of ibrutinib dispersed into a polymer matrix, wherein the polymer matrix is hypromellose;
wherein the solid dispersion formulation provides about 2-fold to about 25-fold increase in average maximum observed concentration in the plasma (C max ) of ibrutinib in a population of healthy human adults in a fasted state compared to a capsule formulation comprising ibrutinib that is not in a solid dispersed composition.
21. The solid dispersion formulation of claim 20 , wherein the solid dispersion formulation provides about 10-fold to about 24-fold increase in the average C max compared to a capsule formulation comprising ibrutinib that is not in a solid dispersed composition.
22. The solid dispersion formulation of claim 20 , wherein the solid dispersion formulation provides about 15-fold to about 19-fold increase in the average C max compared to a capsule formulation comprising ibrutinib that is not in a solid dispersed composition.
23. The solid dispersion formulation of claim 20 , wherein the average C max is about 100 ng/mL to about 1250 ng/mL.
24. The solid dispersion formulation of claim 20 , wherein the average C max is about 200 ng/mL to about 1100 ng/mL.
25. The solid dispersion formulation of claim 20 , wherein the average C max is about 400 ng/mL to about 900 ng/mL.