Pharmaceutical composition containing an anti-nucleating agent
View Patent ↗Pharmaceutical compositions suitable for oral administration in solid dosage forms are described. The compositions comprise an effective amount of a drug compound in the form of a salt, wherein the drug salt is characterized by conversion to a less soluble form of the drug compound under certain pH conditions, and an anti-nucleating agent.
1. A pharmaceutical composition for oral administration as a solid dose, which comprises: (a) from 2 to 15 wt. % of an anti-nucleating agent which comprises a hydroxyalkylcellulose, and (b) from 5 to 75 wt. % of a potassium salt of Compound A, wherein Compound A is:
2. The pharmaceutical composition according to claim 1 , wherein the potassium salt of Compound A is Form 1 potassium salt of Compound A.
3. The pharmaceutical composition according to claim 1 , wherein the anti-nucleating agent comprises hydroxypropylmethylcellulose.
4. The pharmaceutical composition according to claim 1 , which further comprises a first diluent, a second diluent, a disintegrant, and a lubricant.
5. The pharmaceutical composition according to claim 4 , wherein:
the anti-nucleating agent is hydroxypropylmethylcellulose;
the first diluent is microcrystalline cellulose;
the second diluent is lactose or dibasic calcium phosphate;
the disintegrant is croscarmellose sodium; and
the lubricant is magnesium stearate.
6. The pharmaceutical composition according to claim 5 , wherein:
the microcrystalline cellulose is employed in an amount of from 10 to 85 wt. %;
the lactose or dibasic calcium phosphate is employed in an amount of from 10 to 85 wt. %;
the croscarmellose sodium is employed in an amount of from 1 to 10 wt. %; and
the magnesium stearate is employed in an amount of from 0.5 to 10 wt. %.
7. The pharmaceutical composition according to claim 6 , wherein the potassium salt of Compound A is Form 1 potassium salt of Compound A.
8. The pharmaceutical composition according to claim 6 , wherein the composition is encapsulated or compressed into a tablet.
9. The pharmaceutical composition according to claim 8 , wherein the potassium salt of Compound A is employed in an amount of from 5 mg to 900 mg.
10. A process for preparing a compressed tablet having a pharmaceutical composition according to claim 4 , wherein the method comprises:
(A) blending a mixture of the Compound A potassium salt, the anti-nucleating agent, none or all or a first portion of the first diluent, the second diluent, the disintegrant, and a first portion of the lubricant;
(B) either (i) compressing the blended mixture to form one or more slugs or (ii) rolling the blended mixture to form a compact, and then sizing the resulting one or more slugs or the resulting compact to form granules;
(C) blending the granules with all or none or the remaining portion of the first diluent and the remaining portion of the lubricant; and
(D) compressing the lubricated granules of Step C to obtain the tablet.
11. The process according to claim 10 , wherein:
the anti-nucleating agent is hydroxypropylmethylcellulose;
the first diluent is microcrystalline cellulose;
the second diluent is lactose or dibasic calcium phosphate;
the disintegrant is croscarmellose sodium; and
the lubricant is magnesium stearate.
12. The process according to claim 11 , wherein:
the microcrystalline cellulose is employed in an amount of from 10 to 85 wt. %;
the lactose or dibasic calcium phosphate is employed in an amount of from 10 to 85 wt. %;
the croscarmellose sodium is employed in an amount of from 1 to 10 wt. %; and
the magnesium stearate is employed in an amount of from 0.5 to 10 wt. %.
13. A process for preparing a compressed tablet having a pharmaceutical composition according to claim 4 , wherein the method comprises:
(A) wet granulating a mixture of Compound A potassium salt, the anti-nucleating agent, the first diluent, the second diluent, and the disintegrant, and then optionally milling the wet granulated mixture;
(B) drying the wet granulated mixture of Step A;
(C) milling the dried mixture of Step B;
(D) lubricating the milled mixture of Step C with the lubricant; and
(E) compressing the lubricated mixture of Step D into a tablet.
14. A method for improving the pharmacokinetics of a compound of Formula I as recited in claim 1 orally administered in the form of a base salt, wherein the method comprises administering the compound base salt as a component in a solid-dosage pharmaceutical composition that includes an anti-nucleating agent.
15. A method for the treatment of HIV infection in a subject in need thereof which comprises administering to the subject the pharmaceutical composition according to claim 1 .
16. The pharmaceutical composition according to claim 6 , wherein:
the potassium salt of Compound A is employed in an amount of from 5 to 60 wt. %;
the microcrystalline cellulose is employed in an amount of from 15 to 75 wt. %;
the lactose or dibasic calcium phosphate is employed in an amount of from 10 to 50 wt. %;
the croscarmellose sodium is employed in an amount of from 1 to 5 wt. %; and
the magnesium stearate is employed in an amount of from 0.5 to 3 wt. %.
17. The pharmaceutical composition according to claim 16 , wherein the composition is encapsulated or compressed into a tablet.
18. The pharmaceutical composition according to claim 16 , wherein the potassium salt of Compound A is Form 1 potassium salt of Compound A.
19. The pharmaceutical composition according to claim 18 , wherein the composition is encapsulated or compressed into a tablet.
20. The pharmaceutical composition according to claim 3 , wherein the potassium salt of Compound A is employed in an amount of 50 wt. % and the hydroxyproylmethylcellulose is employed in an amount in a range of from 2 wt. % to 15 wt. %.
21. The pharmaceutical composition according to claim 20 , wherein the hydroxyproylmethylcellulose is employed in an amount of 5 wt. %.
22. The pharmaceutical composition according to claim 3 , wherein the hydroxyproylmethylcellulose is a low-viscosity hydroxypropylmethylcellulose.
23. The pharmaceutical composition according to claim 22 , wherein the potassium salt of Compound A is employed in an amount of 50 wt. % and the low-viscosity hydroxyproylmethylcellulose is employed in an amount in a range of from 2 wt. % to 15 wt. %.
24. The pharmaceutical composition according to claim 23 , wherein the low-viscosity hydroxyproylmethylcellulose is employed in an amount of 5 wt. %.
25. The pharmaceutical composition according to claim 1 , wherein the potassium salt of Compound A exhibits improved pharmacokinetic properties when administered as a component of this composition.