Solid pharmaceutical compositions containing an integrase inhibitor
View Patent ↗Compressed tablets for oral administration containing raltegravir in the form of a pharmaceutically acceptable salt are described. The tablets comprise: (A) an intragranular component comprising (i) an effective amount of an alkali metal salt of raltegravir, (ii) optionally a first superdisintegrant, and (iii) a binder; and (B) an extragranular component comprising (i) a second superdisintegrant, (ii) a filler, and (iii) a lubricant. Methods for preparing the tablets and the use of the tablets, optionally in combination with other anti-HIV agents, for the inhibition of HIV integrase, for the treatment or prophylaxis of HIV infection, or for the treatment, delay in the onset, or prophylaxis of AIDS are also described.
1. A compressed tablet for oral administration, which comprises:
(A) an intragranular component comprising:
(i) an effective amount of the potassium salt of raltegravir,
(ii) a first superdisintegrant, and
(iii) a binder; and
(B) an extragranular component comprising:
(i) a second superdisintegrant,
(ii) a filler, and
(iii) a lubricant;
with the proviso that the tablet is free of atazanavir or a pharmaceutically acceptable salt thereof,
wherein:
(A)(i) the potassium salt of raltegravir is employed on a free phenol basis in an amount of at least about 30 wt. %;
(A)(ii) the first superdisintegrant is employed in an amount in a range of from 3 wt. % to about 12 wt. %;
(A)(iii) the binder is employed in an amount in a range of from about 0.5 wt. % to about 7 wt. %;
(B)(i) the second superdisintegrant is employed in an amount in a range of from about 3 wt. % to about 20 wt. %;
(B)(ii) the filler is employed in an amount in a range of from about 10 wt. % to about 40 wt. %; and
(B)(iii) the lubricant is employed in an amount in a range of from about 0.5 wt. % to about 2.5 wt. %;
wherein the total amount of superdisintegrant is in a range of from about 6 wt. % to about 20 wt. %; and
wherein the weight percent of each ingredient in the compressed tablet is based on the total weight of the compressed tablet.
2. The compressed tablet according to claim 1 , wherein:
(A)(i) the potassium salt of raltegravir is employed on a free phenol basis in an amount of at least about 30 wt. %;
(A)(ii) the first superdisintegrant is employed in an amount in a range of from about 3 wt. % to about 12 wt. %;
(A)(iii) the binder is employed in an amount in a range of from about 0.5 wt. % to about 7 wt. %;
(B)(i) the second superdisintegrant is employed in an amount in a range of from about 3 wt. % to about 15 wt. %;
(B)(ii) the filler is employed in an amount in a range of from about 10 wt. % to about 40 wt. %; and
(B)(iii) the lubricant is employed in an amount in a range of from about 0.5 wt. % to about 2.5 wt. %;
wherein the total amount of superdisintegrant is in a range of from about 6 wt. % to about 20 wt. %; and
wherein the weight percent of each ingredient in the compressed tablet is based on the total weight of the compressed tablet.
3. The compressed tablet according to claim 2 , wherein:
(A)(ii) the first superdisintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and combinations thereof;
(A)(iii) the binder has a viscosity in a range of from about 2 to about 100 centipoise (cp) at 20° C. and is selected from the group consisting of HPMC, HPC, PVP and combinations thereof;
(B)(i) the second superdisintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone and combinations thereof;
(B)(ii) the filler is selected from the group consisting of microcrystalline cellulose, mannitol, lactose, Ca phosphate, and combinations thereof; and
(B)(iii) the lubricant is selected from the group consisting of Mg stearate, stearic acid, sodium stearyl fumarate, and combinations thereof.
4. The compressed tablet according to claim 3 , wherein:
(A)(i) the potassium salt of raltegravir is employed in an amount in a range of from about 50 wt. % to about 65 wt. % on a free phenol basis;
(A)(ii) the first superdisintegrant is employed in an amount in a range of from about 5 wt. % to about 10 wt. %;
(A)(iii) the binder is employed in an amount in a range of from about 2 wt. % to about 6 wt. %;
(B)(i) the second superdisintegrant is employed in an amount in a range of from about 6 wt. % to about 12 wt. %;
(B)(ii) the filler is employed in an amount in a range of from about 6 wt. % to about 25 wt. %; and
(B)(iii) the lubricant is employed in an amount in a range of from about 1 wt. % to about 2.5 wt. %;
wherein the total amount of superdisintegrant is in a range of from about 10 wt. % to about 18 wt. %.
5. The compressed tablet according to claim 4 , wherein:
(A)(ii) the first superdisintegrant is intragranular croscarmellose sodium;
(A)(iii) the binder is HPMC;
(B)(i) the second superdisintegrant is extragranular croscarmellose sodium;
(B)(ii) the filler is microcrystalline cellulose or a combination of microcrystalline cellulose and dibasic Ca phosphate; and
(B)(iii) the lubricant is Mg stearate.
6. The compressed tablet according to claim 5 , wherein:
(A)(i) the potassium salt of raltegravir is employed in an amount in a range of from about 55 wt. % to about 60 wt. % on a free phenol basis;
(A)(ii) the intragranular first superdisintegrant is croscarmellose sodium and is employed in an amount in a range of from about 5 wt. % to about 7 wt. %;
(A)(iii) the binder is HPMC and is employed in an amount in a range of from about 3 wt. % to about 5 wt. %;
(B)(i) the extragranular second superdisintegrant is croscarmellose sodium and is employed in an amount in a range of from about 8 wt. % to about 10 wt. %;
(B)(ii) the filler is microcrystalline cellulose and is employed in an amount in a range of from about 16 wt. % to about 18 wt. %; and
(B)(iii) the lubricant is magnesium stearate and is employed in an amount in a range of from about 1 wt. % to about 2 wt. %;
wherein the total amount of croscarmellose sodium is in a range of from about 13 wt. % to about 17 wt. %.
7. The compressed tablet according to claim 5 , wherein:
(A)(i) the potassium salt of raltegravir is employed in an amount in a range of from about 55 wt. % to about 65 wt. % on a free phenol basis;
(A)(ii) the intragranular first superdisintegrant is croscarmellose sodium and is employed in an amount in a range of from about 5 wt. % to about 8 wt. %;
(A)(iii) the binder is HPMC and is employed in an amount in a range of from about 3 wt. % to about 5 wt. %;
(B)(i) the extragranular second superdisintegrant is croscarmellose sodium and is employed in an amount in a range of from about 8 wt. % to about 10 wt. %;
(B)(ii) the filler is a combination of microcrystalline cellulose and dibasic calcium phosphate and is employed in an amount in a range of from about 7 wt. % to about 10 wt. %; and
(B)(iii) the lubricant is magnesium stearate and is employed in an amount in a range of from about 1 wt. % to about 2 wt. % ;
wherein the total amount of croscarmellose sodium is in a range of from about 13 wt. % to about 17 wt. %.
8. The compressed tablet according to claim 1 , wherein the potassium salt of raltegravir is employed on a free phenol basis in an amount in a range of from about 200 mg to about 600 mg per unit dose.
9. The compressed tablet according to claim 5 , which has the following composition:
Relative
Ingredient
Amount (wt. %)
raltegravir K salt
62.1
(57.1 on free phenol basis)
croscarmellose Na (intragranular)
6.2
HPMC2910 (6 cp)
4.1
microcrystalline cellulose, having
17.1
a nominal particle size of about
100 μm, a moisture content of
about 3% to about 5%, and a loose
bulk density of from about 0.26 to
about 0.31 g/cc
croscarmellose Na (extragranular)
9.0
Mg stearate
1.5
Total
100.
10. The compressed tablet according to claim 9 , which has the following composition:
Relative
Unit Dosage
Ingredient
Amount (wt. %)
Amount (mg)
raltegravir K salt
62.1
434.4
(57.1 on free phenol
(=400 mg free
basis)
phenol)
croscarmellose Na
6.2
43.4
(intragranular)
HPMC2910 (6 cp)
4.1
29.0
microcrystalline cellulose,
17.1
119.7
having a nominal particle size
of about 100 μm, a moisture
content of about 3% to about
5%, and a loose bulk density
of from about 0.26 to about
0.31 g/cc
croscarmellose Na
(extragranular)
9.0
63.0
Mg stearate
1.5
10.5
Total
100
700.
11. The compressed tablet according to claim 5 , which has the following composition:
Relative
Ingredient
Amount (wt. %)
raltegravir K salt
70.0
(64.5 on free phenol basis)
croscarmellose Na (intragranular)
7.0
HPMC2910 (6 cp)
4.7
combination of microcrystalline
7.8
cellulose & dibasic Ca phosphate
which is about 75%
microcrystalline cellulose and
about 25% anhydrous dibasic Ca
phosphate in the form of a powder
prepared by the wet dispersion and
spray drying of the cellulose and
the phosphate
croscarmellose Na (extragranular)
9.0
Mg stearate
1.5
Total
100.
12. The compressed tablet according to claim 11 , which has the following composition:
Relative
Unit Dosage
Ingredient
Amount (wt. %)
Amount (mg)
raltegravir K salt
70.0
434.4
(64.5 on free phenol
(400 mg free
basis)
phenol)
croscarmellose Na
7.0
43.4
(intragranular)
HPMC2910 (6 cp)
4.7
29.0
combination of
7.8
48.4
microcrystalline cellulose &
dibasic Ca phosphate which is
about 75% microcrystalline
cellulose and about 25%
anhydrous dibasic Ca
phosphate in the form of a
powder prepared by the wet
dispersion and spray drying of
the cellulose and the
phosphate
croscarmellose Na
9.0
55.8
(extragranular)
Mg stearate
1.5
9.3
Total
100
620.3.
13. The compressed tablet according to claim 10 , wherein the potassium salt of raltegravir is Form 1 crystalline potassium salt of raltegravir.
14. The compressed tablet according to claim 12 , wherein the potassium salt of raltegravir is Form 1 crystalline potassium salt of raltegravir.
15. The compressed tablet of claim 3 , wherein the potassium salt of raltegravir is employed on a free phenol basis in an amount in a range of from about 200 mg to about 600 mg per unit dose.
16. The compressed tablet of claim 4 , wherein the potassium salt of raltegravir is employed on a free phenol basis in an amount in a range of from about 200 mg to about 600 mg per unit dose.
17. The compressed tablet of claim 5 , wherein the potassium salt of raltegravir is employed on a free phenol basis in an amount in a range of from about 200 mg to about 600 mg per unit dose.
18. The compressed tablet of claim 6 , wherein the potassium salt of raltegravir is employed on a free phenol basis in an amount in a range of from about 200 mg to about 600 mg per unit dose.
19. The compressed tablet of claim 15 , wherein the potassium salt of raltegravir is Form 1 crystalline potassium salt of raltegravir.
20. The compressed tablet of claim 16 , wherein the potassium salt of raltegravir is Form 1 crystalline potassium salt of raltegravir.
21. The compressed tablet of claim 17 , wherein the potassium salt of raltegravir is Form 1 crystalline potassium salt of raltegravir.
22. The compressed tablet of claim 18 , wherein the potassium salt of raltegravir is Form 1 crystalline potassium salt of raltegravir.
23. A compressed tablet for oral administration, wherein the compressed tablet comprises:
(A) an intragranular component comprising:
(i) an effective amount of the potassium salt of raltegravir,
(ii) a first superdisintegrant, and
(iii) a binder; and
(B) an extragranular component comprising:
(i) a second superdisintegrant,
(ii) a filler, and
(iii) a lubricant;
and wherein:
(A)(i) the potassium salt of raltegravir is employed on a free phenol basis in an amount of at least about 30 wt. %;
(A)(ii) the first superdisintegrant is employed in an amount in a range of from about 3 wt. % to about 12 wt. %;
(A)(iii) the binder is employed in an amount in a range of from about 0.5 wt. % to about 7 wt. %;
(B)(i) the second superdisintegrant is employed in an amount in a range of from about 3 wt. % to about 20 wt. %;
(B)(ii) the filler is employed in an amount in a range of from about 10 wt. % to about 40 wt. %; and
(B)(iii) the lubricant is employed in an amount in a range of from about 0.5 wt. % to about 2.5 wt. %; and
wherein the total amount of superdisintegrant is in a range of from about 6 wt. % to about 20 wt. %,
wherein the weight percent of each ingredient in the compressed tablet is based on the total weight of the compressed tablet, and wherein the compressed tablet is made by a method comprising:
(A) dry mixing the raltegravir potassium salt, the first superdisintegrant and the binder to obtain a dry blend;
(B) wet granulating the dry blend resulting from Step A, and then optionally milling or sieving the resulting wet granulated mixture;
(C) drying the wet granulated mixture resulting from Step B to obtain dried granules;
(D) milling and sieving the dried granules resulting from Step C;
(E) mixing the milled, sieved granules resulting from Step D with the second superdisintegrant, the filler and the lubricant to obtain a lubricated granular blend; and
(F) compressing the lubricated granular blend resulting from Step E to obtain the compressed tablet,
with the proviso that the process does not employ atazanavir or a pharmaceutically acceptable salt thereof, and that the resulting compressed tablet does not contain atazanavir or a pharmaceutically acceptable salt thereof.
24. The compressed tablet of claim 23 , which comprises:
(A)(i) the potassium salt of raltegravir potassium salt on a free phenol basis in an amount of at least about 30 wt. %;
(A)(ii) the first superdisintegrant in an amount in a range of from about 3 wt. % to about 12 wt. %;
(A)(iii) the binder in an amount in a range of from about 0.5 wt. % to about 7 wt. %;
(B)(i) the second superdisintegrant in an amount in a range of from about 3 wt. % to about 20 wt. %;
(B)(ii) the filler in an amount in a range of from about 10 wt. % to about 40 wt. %; and
(B)(iii) the lubricant in an amount in a range of from about 0.5 wt. % to about 2.5 wt. %;
wherein the total amount of superdisintegrant is in a range of from about 6 wt. % to about 20 wt. %; and
wherein the weight percent of each ingredient in the compressed tablet is based on the total weight of the compressed tablet.
25. The compressed tablet of claim 24 , which comprises:
(A)(i) the potassium salt of raltegravir on a free phenol basis in an amount of at least about 30 wt. %;
(A)(ii) the first superdisintegrant in an amount in a range of from about 3 wt. % to about 12 wt. %;
(A)(iii) the binder in an amount in a range of from about 0.5 wt. % to about 7 wt. %;
(B)(i) the second superdisintegrant in an amount in a range of from about 3 wt. % to about 15 wt. %;
(B)(ii) the filler in an amount in a range of from about 10 wt. % to about 40 wt. %; and
(B)(iii) the lubricant in an amount in a range of from about 0.5 wt. % to about 2.5 wt. %;
wherein the total amount of superdisintegrant is in a range of from about 6 wt. % to about 20 wt. %; and
wherein the weight percent of each ingredient in the compressed tablet is based on the total weight of the compressed tablet.
26. The compressed tablet of claim 25 , wherein:
(A)(ii) the first superdisintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and combinations thereof;
(A)(iii) the binder has a viscosity in a range of from about 2 to about 100 centipoise (cp) at 20° C. and is selected from the group consisting of HPMC, HPC, PVP and combinations thereof;
(B)(i) the second superdisintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone and combinations thereof;
(B)(ii) the filler is selected from the group consisting of microcrystalline cellulose, mannitol, lactose, Ca phosphate, and combinations thereof and
(B)(iii) the lubricant is selected from the group consisting of Mg stearate, stearic acid, sodium stearyl fumarate, and combinations thereof.
27. The compressed tablet of claim 26 , which comprises:
(A)(i) the potassium salt of raltegravir in an amount in a range of from about 50 wt. % to about 65 wt. % on a free phenol basis;
(A)(ii) the first superdisintegrant in an amount in a range of from about 5 wt. % to about 10 wt. %;
(A)(iii) the binder in an amount in a range of from about 2 wt. % to about 6 wt. %;
(B)(i) the second superdisintegrant in an amount in a range of from about 6 wt. % to about 12 wt. %;
(B)(ii) the filler in an amount in a range of from about 6 wt. % to about 25 wt. %; and
(B)(iii) the lubricant in an amount in a range of from about 1 wt. % to about 2.5 wt. %;
wherein the total amount of superdisintegrant is in a range of from about 10 wt. % to about 18 wt. %.
28. The compressed tablet of claim 25 , wherein:
(A)(ii) the first superdisintegrant is intragranular croscarmellose Na;
(A)(iii) the binder is HPMC;
(B)(i) the second superdisintegrant is extragranular croscarmellose Na;
(B)(ii) the filler is microcrystalline cellulose or a combination of microcrystalline cellulose and dibasic Ca phosphate; and
(B)(iii) the lubricant is Mg stearate.
29. The compressed tablet of claim 23 , which comprises:
(A)(i) the potassium salt of raltegravir in an amount in a range of from about 55 wt. % to about 60 wt. % on a free phenol basis;
(A)(ii) the first superdisintegrant is croscarmellose sodium and in an amount in a range of from about 5 wt. % to about 7 wt. %;
(A)(iii) the binder is HPMC and in an amount in a range of from about 3 wt. % to about 5 wt. %;
(B)(i) the second superdisintegrant is croscarmellose sodium and in an amount in a range of from about 8 wt. % to about 10 wt. %;
(B)(ii) the filler is microcrystalline cellulose and in an amount in a range of from about 16 wt. % to about 18 wt. %; and
(B)(iii) the lubricant is magnesium stearate and in an amount in a range of from about 1 wt. % to about 2 wt. % ;
wherein the total amount of croscarmellose sodium is in a range of from about 13 wt. % to about 17 wt. %.
30. The compressed tablet of claim 23 , which comprises:
(A)(i) the potassium salt of raltegravir in an amount in a range of from about 55 wt. % to about 65 wt. % on a free phenol basis;
(A)(ii) the first superdisintegrant is croscarmellose sodium and in an amount in a range of from about 5 wt. % to about 8 wt. %;
(A)(iii) the binder is HPMC and in an amount in a range of from about 3 wt. % to about 5 wt. %;
(B)(i) the second superdisintegrant is croscarmellose sodium and in an amount in a range of from about 8 wt. % to about 10 wt. %;
(B)(ii) the filler is a combination of microcrystalline cellulose and dibasic calcium phosphate and in an amount in a range of from about 7 wt. % to about 10 wt. %; and
(B)(iii) the lubricant is magnesium stearate and in an amount in a range of from about 1 wt. % to about 2 wt. %;
wherein the total amount of croscarmellose sodium is in a range of from about 13 wt. % to about 17 wt. %.
31. The compressed tablet of claim 23 , wherein the potassium salt of raltegravir on a free phenol basis in present in an amount in a range of from about 200 mg to about 600 mg per unit dose.
32. The compressed tablet of claim 23 , which has the following composition:
Relative
Ingredient
Amount (wt. %)
raltegravir K salt
62.1
(57.1 on free phenol basis)
croscarmellose Na (intragranular)
6.2
HPMC2910 (6 cp)
4.1
microcrystalline cellulose, having
17.1
a nominal particle size of about
100 μm, a moisture content of
about 3% to about 5%, and a loose
bulk density of from about 0.26 to
about 0.31 g/cc
croscarmellose Na (extragranular)
9.0
Mg stearate
1.5
Total
100.
33. The compressed tablet of claim 23 , which has the following composition:
Relative
Unit Dosage
Ingredient
Amount (wt. %)
Amount (mg)
raltegravir K salt
62.1
434.4
(57.1 on free phenol
(=400 mg free
basis)
phenol)
croscarmellose Na
6.2
43.4
(intragranular)
HPMC2910 (6 cp)
4.1
29.0
microcrystalline cellulose,
17.1
119.7
having a nominal particle size
of about 100 μm, a moisture
content of about 3% to about
5%, and a loose bulk density
of from about 0.26 to about
0.31 g/cc
croscarmellose Na
(extragranular)
9.0
63.0
Mg stearate
1.5
10.5
Total
100
700.
34. The compressed tablet of claim 23 , which has the following composition:
Relative
Ingredient
Amount (wt. %)
raltegravir K salt
70.0
(64.5 on free phenol basis)
croscarmellose Na (intragranular)
7.0
HPMC2910 (6 cp)
4.7
combination of microcrystalline
7.8
cellulose & dibasic Ca phosphate
which is about 75%
microcrystalline cellulose and
about 25% anhydrous dibasic Ca
phosphate in the form of a powder
prepared by the wet dispersion and
spray drying of the cellulose and
the phosphate
croscarmellose Na (extragranular)
9.0
Mg stearate
1.5
Total
100.
35. The compressed tablet of claim 23 , which has the following composition:
Relative
Unit Dosage
Ingredient
Amount (wt. %)
Amount (mg)
raltegravir K salt
70.0
434.4
(64.5 on free phenol
(400 mg free
basis)
phenol)
croscarmellose Na
7.0
43.4
(intragranular)
HPMC2910 (6 cp)
4.7
29.0
combination of
7.8
48.4
microcrystalline cellulose &
dibasic Ca phosphate which is
about 75% microcrystalline
cellulose and about 25%
anhydrous dibasic Ca
phosphate in the form of a
powder prepared by the wet
dispersion and spray drying of
the cellulose and the
phosphate
croscarmellose Na
9.0
55.8
(extragranular)
Mg stearate
1.5
9.3
Total
100
620.3.
36. The compressed tablet of claim 34 , wherein the potassium salt of raltegravir is the Form 1 crystalline potassium salt of raltegravir.
37. The compressed tablet of claim 1 , wherein disintegration time of said tablet is in a range of from about 5 minutes to about 12 minutes.
38. The compressed tablet according to claim 8 , wherein the potassium salt of raltegravir is employed on a free phenol basis in an amount of about 600 mg per unit dose.
39. The compressed tablet of claim 37 , wherein disintegration time of said tablet is in a range of from about 9 minutes to about 10 minutes.
40. The compressed tablet of claim 1 , wherein one or more of said tablets are administered once daily.
41. The compressed tablet of claim 40 , wherein the one or more of said tablets are administered at or about the same time.
42. The compressed tablet of claim 1 , wherein the hardness of said tablet is about 15 kiloponds.
43. The compressed tablet of claim 38 , wherein one or more of said tablets are administered once daily.
44. The compressed tablet of claim 43 , wherein the one or more of said tablets are administered at or about the same time.
45. The compressed tablet of claim 38 , wherein the hardness of said tablet is about 15 kiloponds.
46. The compressed tablet according to claim 23 , wherein the potassium salt of raltegravir is employed on a free phenol basis in an amount of about 600 mg per unit dose.