DESC:FIELD OF THE INVENTION

The present invention relates to tablet compositions comprising bictegravir, tenofovir alafenamide and emtricitabine.

BACKGROUND OF THE INVENTION
Bictegravir is an integrase strand transfer inhibitor (INSTI). The chemical name of bictegravir sodium is 2,5-Methanopyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, 2,3,4,5,7,9,13,13a-octahydro-8-hydroxy-7,9-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-, sodium salt (1:1), (2R,5S,13aR)-. Bictegravir sodium has a molecular formula of C21H17F3N3NaO5 and a molecular weight of 471.4 and has the following structural formula:

Tenofovir alafenamide, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. The chemical name of tenofovir alafenamide fumarate is L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1). Tenofovir alafenamide fumarate has a molecular formula of C21H29O5N6P•½(C4H4O4) and a molecular weight of 534.5 and has the following structural formula:

Emtricitabine, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI). The chemical name of Emtricitabine is 4-amino-5-fluoro-1-(2R-hydroxymethyl-1,3oxathiolan-5S-yl)-(1H)-pyrimidin-2-one. Emtricitabine has a molecular formula of C8H10FN3O3S and a molecular weight of 247.2 and has the following structural formula:

Combination of bictegravir sodium, tenofovir alafenamide fumarate and emtricitabine is marketed in the form of bilayer tablets under the brand name Biktarvy® by Gilead Sciences Inc in the United States.

U.S Patent No. 9,296,769 assigned to Gilead describes composition comprising tenofovir alafenamide hemifumarate.

U.S Patent publication No. 2017/0189337 assigned to Gilead describes bilayered tablet compositions comprising bictegravir in first layer, tenofovir alafenamide and emtricitabine in second layer.

Inventors of the present invention are developing monolayer tablet compositions comprising bictegravir, tenofovir alafenamide and emtricitabine and one or more pharmaceutically acceptable excipients using simplified process.

SUMMARY OF THE INVENTION
The present invention relates to tablet compositions comprising bictegravir, tenofovir alafenamide, emtricitabine and one or more pharmaceutically acceptable excipients.

One aspect of the present invention is a monolayer tablet composition comprising (a) bictegravir or a pharmaceutically acceptable salt thereof, (b) tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and (c) emtricitabine or a pharmaceutically acceptable salt thereof and (d) one or more pharmaceutically acceptable excipients.

Another aspect of the present invention is a process for preparing monolayer tablet composition comprising:
(a) bictegravir sodium, tenofovir alafenamide fumarate, emtricitabine and at least one excipient were sifted and blended,
(b) blend of step (a) was lubricated using a suitable lubricant,
(c) lubricated blend of step (b) were compacted, milled and sifted to get the desired size granules,
(d) the granules of step (c) were lubricated and finally compressed into tablets.

Another aspect of the present invention is a process for preparing monolayer tablet composition comprising:
(a) tenofovir alafenamide fumarate, emtricitabine and at least one excipient were sifted and blended,
(b) blend of step (a) was lubricated using a suitable lubricant,
(c) lubricated blend of step (b) were compacted, milled and sifted to get the desired size granules,
(d) the granules of step (c) were lubricated using a suitable lubricant,
(e) bictegravir sodium was added extra-granularly to the lubricated granules of step (d) and finally compressed into tablets.

Another aspect of the present invention is a process for preparing monolayer tablet composition comprising:
(a) bictegravir sodium and at least one excipient was sifted and blended,
(b) blend of step (a) was compacted or wet granulated and granules were lubricated using a suitable lubricant,
(c) tenofovir alafenamide fumarate, emtricitabine and at least one excipient were sifted and blended,
(d) blend of step (c) was compacted and granules were lubricated using a suitable lubricant,
(e) granules of step (b) and step (d) were blended and finally compressed into tablets.

Another aspect of the present invention is a method of treating HIV-1 infection in adults comprising administering to the patient, tablets of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to tablet compositions comprising bictegravir, tenofovir alafenamide, emtricitabine and one or more pharmaceutically acceptable excipients.

The term “composition” as used herein refers to a dosage form suitable for oral administration, such as tablets, granules, powder, spheroids, pellets, pills, capsule, solution, suspension, emulsion and the like.

The term “pharmaceutically acceptable” as used herein means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic.

The term “excipients” as used herein means a component of a pharmaceutical product that is not an active ingredient such as, for example, diluents, carriers, binders, disintegrants, lubricants and the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.

Tenofovir alafenamide fumarate as used herein means tenofovir alafenamide monofumarate or tenofovir alafenamide hemifumarate.

One embodiment of the present invention is a monolayer tablet composition comprising (a) bictegravir or a pharmaceutically acceptable salt thereof, (b) tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and (c) emtricitabine or a pharmaceutically acceptable salt thereof and (d) one or more pharmaceutically acceptable excipients.

Another embodiment of the present invention is a monolayer tablet composition comprising (a) bictegravir sodium (b) tenofovir alafenamide fumarate and (c) emtricitabine.

Another embodiment of the present invention is a process for preparing monolayer tablet composition comprising:
(a) bictegravir sodium, tenofovir alafenamide fumarate, emtricitabine and at least one excipient were sifted and blended,
(b) blend of step (a) was lubricated using a suitable lubricant,
(c) lubricated blend of step (b) were compacted, milled and sifted to get the desired size granules,
(d) the granules of step (c) were lubricated and finally compressed into tablets.

Another embodiment of the present invention is a process for preparing monolayer tablet composition comprising:
(a) tenofovir alafenamide fumarate, emtricitabine and at least one excipient were sifted and blended,
(b) blend of step (a) was lubricated using a suitable lubricant,
(c) lubricated blend of step (b) were compacted, milled and sifted to get the desired size granules,
(d) the granules of step (c) were lubricated using a suitable lubricant,
(e) bictegravir sodium was added extra-granularly to the lubricated granules of step (d) and finally compressed into tablets.

Another embodiment of the present invention is a process for preparing monolayer tablet composition comprising:
(a) bictegravir sodium and at least one excipient was sifted and blended,
(b) blend of step (a) was compacted or wet granulated and granules were lubricated using a suitable lubricant,
(c) tenofovir alafenamide fumarate, emtricitabine and at least one excipient were sifted and blended,
(d) blend of step (c) was compacted and granules were lubricated using a suitable lubricant,
(e) granules of step (b) and step (d) were blended and finally compressed into tablets.

The present invention provides a monolayer tablet composition comprising (a) bictegravir or a pharmaceutically acceptable salt thereof, (b) tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and (c) emtricitabine or a pharmaceutically acceptable salt thereof and (d) one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a disintegrant, a lubricant and combinations thereof.
Suitable diluents include, but are not limited to starch, dibasic calcium phosphate, tribasic calcium phosphate, microcrystalline cellulose, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide, lactose monohydrate, sugar alcohols such as mannitol, sorbitol, erythritol and the like and combinations thereof.

Suitable binders include, but are not limited to carbomers, dextrin, ethyl cellulose, hydroxypropyl cellulose, povidone, copovidone, gelatin, polymethacrylates, pregelatinized starch, sodium alginate, gums, synthetic resins, silicic acid and the like and combinations thereof.

Suitable disintegrants include, but are not limited to croscarmellose sodium, sodium starch glycolate, crospovidone, polacrillin potassium, microcrystalline cellulose, carboxymethyl cellulose calcium, starches such as corn starch, potato starch, pre-gelatinized starch and modified starches, clays, bentonite, and the like and combinations thereof.

Suitable lubricants include, but are not limited to calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, and the like and combinations thereof.

One embodiment of the present invention is a method of treating HIV-1 infection in adults comprising administering to the patient the tablets of the present invention.

The monolayer tablet compositions according to the present invention were prepared either by dry granulation process or wet granulation process.
Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which are provided only for purposes of illustration and are not intended to limit the scope of the invention in any manner.

EXAMPLES

Example 1:
S. No Ingredients mg/ tab
Roll Compaction
1 Bictegravir Sodium 52.50
2 Tenofovir alafenamide fumarate 28.00
3 Emtricitabine 200.00
4 Microcrystalline Cellulose 81.00
5 Croscarmellose Sodium 35.00
6 Magnesium Stearate 1.75
Lubrication
7 Magnesium Stearate 1.75
Total weight of core tablet 400.00
8 Opadry white II 85F18422 12.00
Total weight of coated tablet 412.00

Brief manufacturing process:
Step 1: Tenofovir alafenamide fumarate, Bictegravir sodium, Emtricitabine, microcrystalline cellulose and croscarmellose sodium were co-sifted and blended,
Step 2: magnesium stearate was sifted,
Step 3: blend of step 1 were lubricated with sifted material of step 2,
Step 4: blend of step 3 was compacted, using roller compactor, milled and sifted to produce desired size granules,
Step 5: granules of step 4 were lubricated with magnesium stearate and were compressed in to tablets,
Step 6: tablets of step 5 were coated using opadry white coating dispersion.

Example 2:
S. No Ingredients mg/ tab
Roll Compaction
1 Tenofovir alafenamide fumarate 28.00
2 Emtricitabine 200.00
3 Microcrystalline Cellulose 83.50
4 Croscarmellose Sodium 35.00
5 Magnesium Stearate 1.750
Extragranular portion
6 Bictegravir Sodium 52.50
Lubrication
7 Magnesium Stearate 1.75
Total weight of core tablet 402.50
8 Opadry white II 85F18422 12.00
Total weight of coated tablet 414.50

Brief manufacturing process:
Step 1: Tenofovir alafenamide fumarate, Emtricitabine, microcrystalline cellulose and croscarmellose sodium were co-sifted and blended,
Step 2: magnesium stearate was sifted,
Step 3: blend of step 1 were lubricated with sifted material of step 2,
Step 4: blend of step 3 was compacted, using roller compactor, milled and sifted to produce desired size granules,
Step 5: granules of step 4 were blended with Bictegravir sodium and further lubricated with magnesium stearate,
Step 6: lubricated blend of step 5 was compressed in to tablets and prepared tablets were coated with opadry white coating dispersion.

Example 3:
S. No Ingredients mg/ tab
Part - A
1 Bictegravir Sodium 52.50
2 Mannitol 145.30
3 Microcrystalline Cellulose 60.20
4 Sodium Starch Glycolate 15.00
5 Povidone 15.00
6 Purified Water q.s.
Part - B
7 Sodium Starch Glycolate 16.00
8 Microcrystalline Cellulose 50.00
9 Sodium Stearyl Fumarate 6.00
10 Tenofovir alafenamide fumarate 28.00
11 Emtricitabine 200.00
12 Microcrystalline Cellulose 83.50
13 Croscarmellose Sodium 35.00
14 Magnesium Stearate 1.75+1.75
15 Magnesium Stearate 1.75
Total tablet weight (Part A + Part B) 710.00
16 Opadry white II 85F18422 12.00
Total weight of coated tablet 722.00

Brief manufacturing process:
Part A. Bictegravir sodium granules:
Step 1: Bictegravir sodium, microcrystalline cellulose, mannitol and sodium starch glycolate and povidone were co-sifted and blended,
Step 2: blend of step 1, wet granulated using purified water, and the granulated product was dried and milled to get the desired size granules,
Step 3: granules of step 2, were blended with extra-granular sodium starch glycolate and microcrystalline cellulose and further lubricated with sodium stearyl fumarate,

Part - B. Emtricitabine and Tenofovir alafenamide fumarate granules:
Step 1: Tenofovir alafenamide fumarate, Emtricitabine, microcrystalline cellulose and croscarmellose sodium were co-sifted and blended,
Step 2: magnesium stearate was sifted,
Step 3: blend of step 1 were lubricated with sifted material of step 2,
Step 4: blend of step 3 was compacted, using roller compactor, milled and sifted to produce desired size granules,
Step 5: granules of step 4 were lubricated with magnesium stearate.

Compression: Granules obtained in Part A and Part B were blended and compressed into tablets and prepared tablets were coated with opadry white coating dispersion.

Example 4:
S. No Ingredients mg/ tab
Part - A
1 Bictegravir Sodium 52.50
2 Microcrystalline Cellulose 214.70
3 Croscarmellose Sodium 19.00
4 Magnesium Stearate 2.40
Part - B
5 Tenofovir alafenamide fumarate 28.04
6 Emtricitabine 200.00
7 Microcrystalline Cellulose 113.06
8 Croscarmellose Sodium 30.45
9 Magnesium Stearate 2.85
Total tablet weight (Part A + Part B) 663.00
11 Opadry white II 85F18422 17.00
Total weight of coated tablet 680.00

Brief manufacturing process:
Part A. Bictegravir sodium granules:
Step 1: Bictegravir sodium, microcrystalline cellulose and croscarmellose sodium were co-sifted and blended,
Step 2: magnesium stearate was sifted,
Step 3: blend of step 1 were lubricated with sifted material of step 2,
Step 4: blend of step 3 was compacted, using roller compactor, milled and sifted to produce desired size granules,

Part - B. Emtricitabine and Tenofovir alafenamide fumarate granules:
Step 1: Tenofovir alafenamide fumarate, Emtricitabine, microcrystalline cellulose and croscarmellose sodium were co-sifted and blended,
Step 2: magnesium stearate was sifted,
Step 3: blend of step 1, lubricated with sifted material of step 2,
Step 4: blend of step 3 was compacted using roller compactor, milled and sifted to produce desired size granules,
Step 5: granules of step 4 were lubricated with magnesium stearate.

Compression: Granules obtained in Part A and Part B were blended and compressed into tablets and prepared tablets were coated with opadry white coating dispersion.

Example 5:
S. No Ingredients mg/ tab
Part - A
1 Bictegravir Sodium 52.5
2 Microcrystalline Cellulose 246.7
3 Croscarmellose Sodium 19.0
4 Magnesium stearate 4.8
Part - B
5 Emtricitabine 200.00
6 Tenofovir alafenamide fumarate 28.043
7 Microcrystalline Cellulose 113.06
8 Croscarmellose Sodium 30.2
9 Magnesium stearate 5.7
Total tablet weight (Part A + Part B) 700.00
10 Opadry II white 85F18422 21.0
Total weight of coated tablet 721.00

Brief manufacturing process:
Part A. Bictegravir granules:
Step 1: Bictegravir sodium, first part of microcrystalline cellulose and croscarmellose sodium were co-sifted and blended,
Step 2: first part of magnesium stearate was sifted,
Step 3: blend of step 1, were lubricated with sifted material of step 2,
Step 4: blend of step 3, was compacted using roller compactor, milled and sifted to produce desired size granules,
Step 5: prepared granules of step 4 were blended, with second part of microcrystalline cellulose
Step 6: second part of magnesium stearate was sifted,
Step 7: the blend of step 5, were lubricated with second part of magnesium stearate.

Part - B. Emtricitabine and Tenofovir alafenamide fumarate granules:
Step 1: Tenofovir alafenamide fumarate, Emtricitabine, microcrystalline cellulose and croscarmellose sodium were co-sifted and blended,
Step 2: first part of magnesium stearate was sifted,
Step 3: blend of step 1, were lubricated with sifted material of step 2
Step 4: blend of step 3, was compacted using roller compactor, milled and sifted to produce desired size granules,
Step 5: granules of step 4 were lubricated with second part of magnesium stearate.

Compression: Granules obtained in Part A and Part B were blended and compressed into tablets and prepared tablets were coated with using Opadry white dispersion.

Comparison of Dissolution profile of Example 5 with Biktarvy® tablets:

Table A:
Time points
(Minutes) % of drug release
(Biktarvy® tablets)
Bictegravir
Sodium Emtricitabine Tenofovir Alafenamide
Fumarate
5 40 64 56
10 66 98 101
15 79 102 104
20 86 103 105
30 93 103 105
45 98 102 105

Table B:
Time points
(Minutes) % of drug release
(Test results of Example 5)
Bictegravir
Sodium Emtricitabine Tenofovir Alafenamide
Fumarate
5 44 77 77
10 76 97 99
15 86 96 99
20 90 96 99
30 94 97 100
45 95 97 100

Biktarvy® tablets were bilayered tablets, whereas tablets of the present invention prepared as mono-layered tablets. From Table A and Table B, it is revealed that there is an improvement in the drug release for tablets of the present invention.

Table C:
Results of stability evaluation of Bictegravir Sodium, Emtricitabine and Tenofovir Alafenamide Fumarate tablets prepared from Example 5:

Packaging Configuration Specification HDPE (3g Silica canister +
polyester coil)
Condition Initial Stability Initial 3M- 40/75 6M-
40/75
Emtricitabine
Emtricitabine-RC-02 0.2% 0.2% 0.019 0.033 0.038
Emtricitabine-RC-04 0.2% 0.5% 0.005 0.010 0.024
Tenofovir Alafenamide
Tenofovir RC-01 1.5% 3.0% 0.166 1.285 1.646
Tenofovir RC-07 0.5% 2.5% 0.041 1.022 2.235
Tenofovir RC-02 0.5% 0.5% 0.054 0.096 0.119
Highest Unknown 2.0% 2.0% 0.037 0.033 0.032
Bictegravir
Bictegravir Hydroxy Analog 0.4% 0.4% 0.038 0.042 0.044
Highest Unknown - - 0.109 0.116 0.120

The pharmaceutical composition of the present invention having three active agents as per Example 5 is found to be stable.
,CLAIMS:WE CLAIM:

1. A monolayer tablet composition comprising, (a) bictegravir or a pharmaceutically acceptable salt thereof, (b) tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and (c) emtricitabine or a pharmaceutically acceptable salt thereof and (d) one or more pharmaceutically acceptable excipients.

2. The tablet composition according to claim 1, comprises bictegravir in the form of bictegravir sodium.

3. The tablet composition according to claim 1, comprises tenofovir alafenamide in the form of tenofovir alafenamide fumarate.

4. The monolayer tablet composition of claim 1, wherein one or more pharmaceutically acceptable excipients are selected from a diluent, a binder, a disintegrant, a lubricant and combinations thereof.

5. The monolayer tablet composition of claim 1, is prepared either by dry granulation process or wet granulation process.

6. A process for preparing monolayer pharmaceutical tablet comprising:
(a) sifting and blending bictegravir sodium, tenofovir alafenamide fumarate, emtricitabine and at least one excipient,
(b) lubricating the blend of step (a) using a suitable lubricant,
(c) compacting the lubricated blend of step (b) followed by milling and sifting to get the desired size granules,
(d) lubricating the granules of step (c) and finally compressing in to tablets.

7. A process for preparing monolayer tablet composition comprising:
(a) sifting and blending tenofovir alafenamide fumarate, emtricitabine and at least one excipient, (b) lubricating the blend of step (a) using a suitable lubricant,
(c) compacting the lubricated blend of step (b) followed by milling and sifting to get the desired size granules,
(d) lubricating the granules of step (c) using a suitable lubricant,
(e) adding bictegravir sodium extragranularly to the lubricated granules of step (d) and finally compressing in to tablets.

8. A process for preparing monolayer tablet composition comprising:
(a) sifting and blending bictegravir sodium and at least one excipient,
(b) compacting or wet granulating the blend of step (a) and lubricating the resulted granules using a suitable lubricant,
(c) sifting and blending tenofovir alafenamide fumarate, emtricitabine and at least one excipient, (d) compacting the blend of step (c) and lubricating the resulted granules using a suitable lubricant,
(e) blending the granules of step (b) and step (d) and finally compressing in to tablets.

9. The process of claim 6, 7 and 8, wherein at least one excipient is selected from a diluent, a disintegrant and combinations thereof.

10. The method of treating HIV-1 infection in adults comprising administering to the patient the tablet of claim 1.

Dated this Twenty-fifth (25th) day of March, 2019

Signature: ----------------------------------------------------------
Name: Dr. KHADGAPATHI PODILE
EXECUTIVE DIRECTOR
HETERO LABS LIMITED