Claims for Patent: 10,603,282

Summary for Patent: 10,603,282

Title:	Pharmaceutical compositions containing doravirine, tenofovir disoproxil fumarate and lamivudine
Abstract:	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.
Inventor(s):	Panmai; Santipharp (Cranford, NJ), Tatavarti; Aditya (Chalfont, PA), Farrington; Andrew M. (Collegeville, PA), Biyyala; Varsha (Somerset, NJ), Allain; Leonardo R. (Lansdale, PA), Nefliu; Marcela (Schwenksville, PA), Klinzing; Gerard R. (Wilmington, DE), Ren; Jie (Chalfont, PA), Lamm; Matthew (Morristown, NJ)
Assignee:	Merck Sharp & Dohme Corp. (Rahway, NJ)
Application Number:	15/780,142
Patent Claims:	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: TABLE-US-00012 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: TABLE-US-00013 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: TABLE-US-00014 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.