Solid pharmaceutical compositions containing an integrase inhibitor
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 method for the treatment or prophylaxis of HIV infection or the treatment, prophylaxis or delay in the onset of AIDS in a subject in need thereof which comprises administering to the subject 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 croscarmellose sodium and is employed in an amount in a range of from 3 wt. % to about 12 wt. %;
(A)(iii) the binder is HPMC and is employed in an amount in a range of from about 0.5 wt. % to about 7 wt. %;
(B)(i) the second superdisintegrant is croscarmellose sodium and is employed in an amount in a range of from about 3 wt. % to about 20 wt. %;
(B)(ii) the filler is microcrystalline cellulose and is employed in an amount in a range of from about 10 wt. % to about 40 wt. %; and
(B)(iii) the lubricant is magnesium stearate and 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 croscarmellose sodium 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 method according to claim 1 , wherein the compressed tablet comprises:
(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. %.
3. The method according to claim 1 , wherein the compressed tablet comprises:
(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. %.
4. The method according to claim 1 wherein, in the compressed tablet, the potassium salt of raltegravir is Form 1 crystalline potassium salt of raltegravir.
5. The method according to claim 2 wherein, in the compressed tablet, the potassium salt of raltegravir is Form 1 crystalline potassium salt of raltegravir.
6. The method according to claim 3 wherein, in the compressed tablet, the potassium salt of raltegravir is Form 1 crystalline potassium salt of raltegravir.
7. The method according to claim 1 , wherein, in the compressed tablet, 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.
8. The method according to claim 2 wherein, in the compressed tablet, 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 method according to claim 3 wherein, in the compressed tablet, 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.
10. The method according to claim 7 wherein, in the compressed tablet, the potassium salt of raltegravir is employed on a free phenol basis in an amount of about 600 mg per unit dose.
11. The method according to claim 1 , wherein one or more of said tablets are administered once daily.
12. The method according to claim 10 , wherein the one or more of said tablets are administered at or about the same time.
13. The method according to claim 2 , wherein the compressed tablet has the following composition:
Ingredient
Relative 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.
14. The method according to claim 2 , wherein the compressed tablet 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
9.0
63.0
(extragranular)
Mg stearate
1.5
10.5
Total
100
700.
15. The method according to claim 13 wherein, in the compressed tablet, the potassium salt of raltegravir is Form 1 crystalline potassium salt of raltegravir.
16. The method according to claim 14 wherein, in the compressed tablet, the potassium salt of raltegravir is Form 1 crystalline potassium salt of raltegravir.