Pharmaceutical compositions containing doravirine, tenofovir disoproxil fumarate and lamivudine
The instant invention relates to pharmaceutical compositions comprising doravirine, tenofovir disoproxil fumarate and lamivudine. These compositions are useful for the treatment of HIV infection. Also disclosed are processes for making said pharmaceutical compositions.
1. A pharmaceutical composition, which is a bilayer tablet, comprising an amorphous dispersion formulation of doravirine in the first layer, and lamivudine and tenofovir disoproxil fumarate in the second layer.
2. The pharmaceutical composition of claim 1 wherein the amorphous dispersion formulation of doravirine comprises doravirine and a polymer.
3. The pharmaceutical composition of claim 2 wherein the polymer is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, hydroxpropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate, polyvinylpyrrolidinone and polyvinylpyrrolidinone-polyvinylacetate copolymers.
4. The pharmaceutical composition of claim 3 wherein the polymer is hydroxypropyl methyl cellulose acetate succinate.
5. The pharmaceutical composition of claim 1 wherein the first layer comprises an amorphous dispersion formulation of doravirine, a glidant, a diluent, a disintegrant, and a lubricant.
6. The pharmaceutical composition of claim 5 wherein the first layer comprises a glidant that is selected from the group consisting of colloidal silica, silicone dioxide, talc and starch; a diluent that is selected from the group consisting of lactose, lactose anhydrous, lactose monohydrate, mannitol, microcrystalline cellulose, calcium phosphate dibasic, calcium carbonate and magnesium carbonate; a disintegrant that is selected from the group consisting of croscarmellose sodium, starch, crospovidone, and sodium starch glycolate; and a lubricant that is selected from the group consisting of magnesium stearate, stearic acid or sodium stearyl fumarate.
7. The pharmaceutical composition of claim 6 wherein the first layer comprises a glidant that is colloidal silica; a diluent that is microcrystalline cellulose; a disintegrant that is croscarmellose sodium; and a lubricant that is magnesium stearate.
8. The pharmaceutical composition of claim 1 wherein the second layer comprises lamivudine, tenofovir disoproxil fumarate, a glidant, a diluent, a disintegrant, and lubricants.
9. The pharmaceutical composition of claim 8 wherein the second layer comprises a glidant that is selected from the group consisting of colloidal silica, silicone dioxide, talc and starch; a diluent that is selected from the group consisting of lactose, lactose anhydrous, lactose monohydrate, mannitol, microcrystalline cellulose, calcium phosphate dibasic, calcium carbonate and magnesium carbonate; a disintegrant that is selected from the group consisting of croscarmellose sodium, starch, crospovidone, and sodium starch glycolate; lubricants that are selected from the group consisting of magnesium stearate, stearic acid and sodium stearyl fumarate.
10. The pharmaceutical composition of claim 9 wherein the second layer comprises a glidant that is colloidal silica; a diluent that is microcrystalline cellulose; a disintegrant that is croscarmellose sodium; and lubricants that are magnesium stearate and sodium stearyl fumarate.
11. The pharmaceutical composition of claim 1 wherein lamivudine and tenofovir disoproxil fumarate are co-granulated.
12. The pharmaceutical composition of claim 1 wherein lamivudine and tenofovir disoproxil fumarate are separately granulated.
13. The pharmaceutical composition of claim 1 comprising a film coat.
14. The pharmaceutical composition of claim 1 comprising a polishing aid.
15. The pharmaceutical composition of claim 1 comprising 50 mg of doravirine, 150 mg of lamivudine and 150 mg of tenofovir disoproxil fumarate.
16. The pharmaceutical composition of claim 1 comprising 100 mg of doravirine, 300 mg of lamivudine and 300 mg of tenofovir disoproxil fumarate.
17. The pharmaceutical composition of claim 1 comprising:
Amount
Components
[mg]
Layer 1
Intragranular
Doravirine
50.00
Hypromellose acetate succinate -
200.0
LG (HPMC-ASLG)
Microcrystalline Cellulose
107.5
Lactose Monohydrate
107.5
Croscarmellose Sodium
15.00
Colloidal Silica
2.50
Magnesium Stearate
1.25
Extragranular
Croscarmellose Sodium
15.00
Magnesium Stearate
1.25
Layer 1 Weight
500.0
Layer 2
Intragranular
Lamivudine
150.0
Tenofovir Disoproxil Fumarate
150.0
Microcrystalline Cellulose
120.0
Lactose Monohydrate
55.0
Croscarmellose Sodium
10.00
Magnesium Stearate
1.25
Extragranular
Croscarmellose Sodium
10.00
Magnesium Stearate
3.75
Layer 2 Weight
500.0
Core Tablet Weight
1000.0
Opadry II 39K Film Coat
25.00
Film-Coated Tablet Weight
1025.0.
18. The pharmaceutical composition of claim 1 comprising:
Amount
Components
[mg]
Layer 1
Intragranular
Doravirine
100.0
Hypromellose acetate succinate -
400.0
LG (HPMC-ASLG)
Microcrystalline Cellulose
224.0
Croscarmellose Sodium
24.0
Colloidal Silica
4.00
Magnesium Stearate
2.00
Extragranular
Croscarmellose Sodium
24.00
Magnesium Stearate
2.00
Layer 1 Weight
780.0
Layer 2
Intragranular
Lamivudine
300.0
Tenofovir Disoproxil Fumarate
300.0
Microcrystalline Cellulose
103.8
Croscarmellose Sodium
23.4
Colloidal Silica
7.80
Magnesium Stearate
7.80
Sodium Stearyl Fumarate
7.80
Extragranular
Croscarmellose Sodium
23.40
Magnesium Stearate
6.00
Layer 2 Weight
780.0
Core Tablet Weight
1560
Opadry II 39K Film Coat
39.00
Carnauba Wax
0.05
Film-Coated Tablet Weight
1599.
19. The pharmaceutical composition of claim 1 comprising:
Amount
Components
[mg]
Layer 1
Intragranular
Doravirine
100.0
Hypromellose acetate succinate -
400.0
LG (HPMC-ASLG)
Microcrystalline Cellulose
224.0
Croscarmellose Sodium
24.0
Colloidal Silica
4.00
Magnesium Stearate
2.00
Extragranular
Croscarmellose Sodium
24.00
Magnesium Stearate
2.00
Layer 1 Weight
780
Layer 2
Intragranular
Tenofovir Disoproxil Fumarate
300.0
Microcrystalline Cellulose
51.93
Croscarmellose Sodium
11.70
Colloidal Silica
3.12
Sodium Stearyl Fumarate
4.50
Magnesium Stearate
4.50
Intragranular
Lamivudine
300.0
Microcrystalline Cellulose
55.68
Croscarmellose Sodium
11.70
Colloidal Silica
3.12
Sodium Stearyl Fumarate
2.25
Magnesium Stearate
2.25
Extragranular
Croscarmellose Sodium
23.40
Magnesium Stearate
6.00
Layer 2 Weight
780
Core Tablet Weight
1560
Opadry II 39K Film Coat
39.00
Film-Coated Tablet Weight
1599.