DESC:

FIELD OF INVENTION
The present invention provides oral pharmaceutical compositions comprising tenofovir alafenamide pharmaceutically acceptable salt optionally in combination with one or more anti-retroviral agents and one or more pharmacokinetic booster or enhancer. The present invention provides oral pharmaceutical compositions of tenofovir alafenamide succinate in combination with one or more anti-viral drug and one or more pharmaceutically acceptable excipients. The present invention also provides the manufacturing process thereof and use of the said compositions for the prevention, treatment or prophylaxis of diseases caused by viruses specifically caused by retroviruses or hepatitis B virus.

BACKGROUND
Human immunodeficiency virus (HIV) is an infectious virus that attacks the host’s immune system. This makes HIV infected patients more vulnerable to illness like tuberculosis, secondary infections, and some cancers. HIV infection is treated with antiretroviral drugs, which inhibit the virus replication. The current standard of care for the treatment of HIV-1 infection employs a combination antiretroviral therapy (ART) to suppress viral replication to below detectable limits, augment CD4 cell counts, and slow down disease progression.

There are seven major classes of antiretroviral drugs based on mechanism of action, each of which interferes with virus replication in different ways. These drugs generally classified according to the phase of the HIV life cycle inhibited by them. Most common combinations include two nucleoside reverse transcriptase inhibitors (NRTIs), at least one non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), integrase inhibitor (II)or a pharmacokinetic enhancer. Various drug regulating authorities such as the United States Food and Drug Administration (USFDA), European Medicines Agency (EMA) has approved several antiretroviral drugs and its fix dose combination (FDC) to treat HIV infection.
One of the nucleoside reverse transcriptase inhibitors (NRTIs)approved by drug regulating authority is Tenofovir Alafenamide. It is a lipophilic prodrug of Tenofovir. It is used for the treatment of HIV, chronic hepatitis B virus (HBV) as a monotherapy and given in combination with other anti-viral medications for the treatment of HIV infection.
Tenofovir alafenamide containing oral product approved by drug regulatory authority includes tenofovir alafenamide fumarate combinations with other drugs like emtricitabine, rilpivirine, cobicistat, elvitegravir, darunavir and bictegravir.
The PCT application 2017004244 discloses an oral dosage form of tenofovir alafenamide hemi-fumarate, emtricitabine and tenofovir alafenamide hemi-fumarate, emtricitabine,rilpivirine. The application specifically discloses a composition of tenofovir alafenamide hemi-fumarate with tablet weight of about 300mg±25mg and mentions that higher drug loads were achieved by reducing the total tablet weight from 450 mg to 350 mg.
The PCT application 2013116720 discloses a combination of tenofovir alafenamide hemi-fumarate, cobicistat, emtricitabine, elvitegravir and combination of tenofovir alafenamide hemi-fumarate, cobicistat, emtricitabine, darunavir. The PCT application 2017083304 discloses solid oral dosage forms of tenofovir alafenamide hemi-fumarate withbictegravir andemtricitabine for the treatment of HIV.
The present invention provides an alternative pharmaceutical composition of tenofovir alafenamide pharmaceutical salt. The present invention provides a stabletablet composition of tenofovir alafenamide succinate. The inventors of the present invention have surprisingly found that the stability of compositions comprising tenofovir alafenamide succinate does not depend on the tablet weight. The present invention provides a stable composition of tenofovir alafenamide succinate and its combination with one or more other anti-retroviral agents with total tablet weight more than450 mg, preferably more than 500 mg, more than 650 mg, and more than 700 mg.
SUMMARY OF INVENTION
The present invention provides oral pharmaceutical compositions of tenofovir alafenamide succinate and its combination thereof. The present invention provides a stable oral pharmaceutical composition of tenofovir alafenamide succinate and emtricitabine. The present invention provides pharmaceutical composition of rilpivirine hydrochloride, tenofovir alafenamide succinate and emtricitabine.
The present invention provides an oral pharmaceutical composition comprising about 12 mg to 32 mg of tenofovir alafenamide succinate which is equivalent to about 10 mg to 25 mg of tenofovir alafenamide. The proportion of tenofovir alafenamide succinate in the composition is from about 2.0 -7.0 % by weight. The present invention further provides a solid oral dosage form which has a total weight of more than 450 mg, more than 500 mg, more than 650 mg, more than 700 mg.
The present invention provides anoral pharmaceutical composition comprising 12 mg to 32 mg of tenofovir alafenamide succinate, equivalent to 10 mg to 25 mg of tenofovir alafenamide and 200 mg of emtricitabine. The proportion of tenofovir alafenamide succinate in the composition is from about 2.0% to about 7.0 % by weight. The solid oral dosage form has total weight of more than 450 mg, more than 500 mg, more than 650 mg, more than 700 mg.
The present invention provides an oral pharmaceutical composition comprising rilpivirine hydrochloride, tenofovir alafenamide succinate and emtricitabine. Theoral pharmaceutical composition has total weight of more than 450 mg, more than 500 mg, more than 650 mg, more than 700 mg.
The present invention provides anoral pharmaceutical composition comprising 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine. The solid oral dosage form has total weight of more than 450 mg, more than 500 mg, more than 650 mg, more than 700 mg.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an oral pharmaceutical composition of tenofovir alafenamide succinate. The present invention provides an oral pharmaceutical composition of tenofovir alafenamide succinate that includes its hydrates such as monohydrate, dihydrate, polymorphsuch as crystalline and amorphous, cocrystal such as mono-succinate, hemi-succinate and all ratios of tenofovir alafenamide to succinate from 0.1 to 1 and 1 to 0.1. The present invention provides an oral pharmaceutical composition of tenofovir alafenamide succinate in combination with one or more anti-retroviral agents and/or one or more pharmacokinetic booster or enhancer. The present invention provides an oral pharmaceutical composition of tenofovir alafenamide succinate and its combinations with one or more anti-retroviral agentand with one or more pharmaceutically acceptable excipients.
The present invention also provides the manufacturing process thereof and use of the said compositions for the prevention, treatment or prophylaxis of diseases caused by viruses specifically caused by retroviruses or hepatitis B virus.
The present invention provides an oral pharmaceutical composition of tenofovir alafenamide succinate and its combination with one or more anti-retroviral agents and/or one or more pharmacokinetic booster or enhancer such as emtricitabine, rilpivirine, bictegravir, elvitegravir, cobicistat, darunavir, efavirenz, lamivudine, elvitegravir; zidovudine, abacavir, lopinavir, ritonavir, dolutegravir, abacavir, atazanavir doravirine; dapivirine’ elsulfavirine nevirapine, romidepsin, besifovir, entecavir, telbivudine, filocilovir, pradefovir, clevudine, ribavirin, famciclovir, metacavir. adefovir, adefovir dipivoxil, azvudine, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudinetidoxil, dapivirine, etravirine, fozivudinetidoxil, islatravir, stavudine, zalcitabine, zidovudine, rovafoviretalafenamide pharmaceutically acceptable salts.
The present invention provides an oral pharmaceutical composition of tenofovir alafenamide succinate and its combination with one or more of agent selected from emtricitabine,rilpivirine, cobicistat, darunavir and bictegravir,
The solid oral pharmaceutical composition may be in any form known in the art. The preferred solid oral dosage form is a tablet. The tablets may be in the form of a monolayer tablet, or a multilayer tablet. The present invention provides oral tablets of tenofovir alafenamide succinate and its combinations and with one or more pharmaceutically acceptable excipients.
The present invention provides tablets of tenofovir alafenamide succinate and its combinations with one or more pharmaceutically acceptable excipients. Excipients should be compatible with the other ingredients of the composition and physiologically innocuous to the recipient thereof.
As used herein the term "excipients" is intended to refer to solubilizers, glidants, fillers, binders, lubricant, diluents, preservatives, surface active agents, basifying agents, dispersing agents and the like. The term also includes agents such as sweetening agents, flavoring agents, coloring agents, and preserving agents.
As used herein, the term “about” means an acceptable change for a particular value as determined by those skilled in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” means within 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

Where an indefinite or definite article is used when referring to a singular noun, e.g. “a”, “an” or “the”, this includes a plural of that noun unless something else is specifically stated.

As used herein the term "excipients" and “pharmaceutically acceptable excipients” is intended to refer to solubilizers, glidants, fillers, binders, lubricant, diluents, preservatives, surface active agents, basifying agents, dispersing agents and the like. The term also includes agents such as sweetening agents, flavoring agents, coloring agents and preserving agents.
Examples of lubricants, glidants and flow aids include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl behenate, sodium stearyl fumarate, colloidal silicon dioxide, and talc. In certain specific embodiments, tablets of the invention include magnesium stearate.
Examples of solubilizes include, but are not limited to, ionic surfactants (including both ionic and nonionic surfactants) such as sodium lauryl sulphate, cetyltrimethylammonium bromide, polysorbates (such as polysorbate 20 or 80), poloxamers (such as poloxamer 188 or 207), and macrogols.
Examples of disintegrants include, but are not limited to, starches, celluloses, cross-linked povidone, povidone, sodium starch glycolate, croscarmellose sodium.
Examples of fillers (also known as bulking agents or diluents) include, but are not limited to, starches, maltodextrins, polyols (such as lactose), and celluloses (such as microcrystalline cellulose). Tablets provided herein may include lactose and/or microcrystalline cellulose. Lactose can be used in anhydrous or hydrated form.
Examples of binders include, but are not limited to, cross-linked povidone, HPMC, microcrystalline cellulose, sucrose, starches, etc.
Tablets provided herein may be uncoated or film coated. Film coatings are known in the art and can be composed of hydrophilic polymer materials, but are not limited to, polysaccharide materials, such as hydroxypropylmethyl cellulose (HPMC), methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), poly(vinylalcohol-co-ethylene glycol) and other water-soluble polymers. The coating may be white or coloured. Suitable coatings include, but are not limited to, polymeric film coatings such as those comprising polyvinyl alcohol e.g. 'Opadry® TF’, which includes part-hydrolysedpolyvinylalcohol, titanium dioxide, macrogol 3350 and talc, with optional colouring such as iron oxide or indigo carmine or iron oxide yellow or yellow. The amount of coating is about 2-4% of the core tablet weight.
In one embodiment, the present invention provides solid oral dosage forms of tenofovir alafenamide succinate and one or more pharmaceutically acceptably excipients.
In another embodiment, the present invention provides an oralpharmaceutical composition comprising about 12 mg to 32 mg of tenofovir alafenamide succinate equivalent to about 10 mg to 25 mg of tenofovir alafenamide. The proportion of tenofovir alafenamide succinate in the composition is from about 2.0 -7.0 % by weight.
In a particular embodiment, the present invention provides an oral pharmaceutical composition which has a total weight of more than 450 mg, more than 500 mg, more than 650 mg, more than 700 mg. In a further embodiment’ the present invention provides an oral pharmaceutical composition which has a total weight of 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg to 650 mg, 650 mg to 700 mg, 700mg to 750 mg. In another embodiment, the present invention provides an oral pharmaceutical composition which has a total weight of 450 mg ± 50 mg, 500 mg ± 50 mg, 550 mg ± 50 mg, 600 mg ± 50 mg, 650 mg ± 50 mg, 700 mg ± 50 mg, 750 ± 50 mg. In another embodiment, the present invention provides an oral pharmaceutical composition which has a total weight of 450 mg ± 25 mg, 500 mg ± 25 mg, 550 mg ± 25 mg, 600 mg ± 25 mg, 650 mg ± 25 mg, 700 mg ± 25 mg, 750 ± 25 mg. In another embodiment, the present invention provides an oral pharmaceutical composition which has a total weight of 450 mg ± 15 mg, 500 mg ± 15 mg, 550 mg ± 15 mg, 600 mg ± 15 mg, 650 mg ± 15 mg, 700 mg ± 15 mg, 750 ± 15 mg.
In one embodiment, the present invention provides a solid oral dosage form comprising tenofovir alafenamide succinate, emtricitabine and one or more pharmaceutically acceptably excipients.
In another embodiment, the present invention provides an oral pharmaceutical composition comprising 12 mg to 32 mg of tenofovir alafenamide succinate, equivalent to 10 mg to 25 mg of tenofovir alafenamide and 200 mg of emtricitabine, and one or more pharmaceutically acceptably excipients. The proportion of tenofovir alafenamide succinate in the composition is about 2.0% to about 7.0 % by weight.
In an embodiment, the present invention provides a tablet comprising 12 to 32 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, and one or more pharmaceutically acceptably excipient, wherein the tablet comprises about 2.0% to about 7.0 % by weight of tenofovir alafenamide succinate.
In an embodiment, the present invention provides a tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, and one or more pharmaceutically acceptably excipient,wherein the tablet has about 2.0% to about 7.0 % by weight of tenofovir alafenamide succinate.
In an embodiment, the present invention provides a film coated tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, and one or more pharmaceutically acceptably excipients, wherein the tablet has about 2.0% to about 7.0 % by weight of tenofovir alafenamide succinate.
In an embodiment, the present invention provides a tablet comprising 12 to 32 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, and one or more pharmaceutically acceptably excipients, wherein the tablet has a total weight of 500mg± 15 mg.
In an embodiment, the present invention provides a tablet comprising 12 to 32 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 450mg± 15 mg.
In an embodiment, the present invention provides a tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 500mg± 15 mg.
In an embodiment, the present invention provides a film coated tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 500mg± 15 mg.

In an embodiment, the present invention provides a tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 450 mg± 15 mg.
In an embodiment, the present invention provides a film coated tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 450 mg± 15 mg.
In a specific embodiment, the present invention provides a tablet comprising12.5 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, and one or more pharmaceutically acceptably excipient, wherein the tablet comprises about 2.0% to about 3.0 %by weight of tenofovir alafenamide succinate.
In a specific embodiment, the present invention provides a tablet consisting of 12.5 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine,and one or more pharmaceutically acceptably excipient, wherein the tablet hasabout 2.0% to about 3.0 % by weight of tenofovir alafenamide succinate.
In a specific embodiment, the present invention provides a film coated tablet consisting of 12.5 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine,and one or more pharmaceutically acceptably excipient, wherein the tablet hasabout 2.0% to about 3.0 % by weight of tenofovir alafenamide succinate.
In a specific embodiment, the present invention provides a tablet comprising 12.5 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 500mg± 15 mg.
In a specific embodiment, the present invention provides a tablet comprising 12.5 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 450mg± 15 mg.
In a specific embodiment, the present invention provides a tablet consisting of 12.5 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 500mg± 15 mg.
In a specific embodiment, the present invention provides a film coated tablet consisting of 12.5 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 500mg± 15 mg.
In a specific embodiment, the present invention provides a tablet consisting of 12.5 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 450mg± 15 mg.
In a specific embodiment, the present invention provides a film coated tablet consisting of 12.5 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 450mg± 15 mg.
In another embodiment, the present invention provides a tablet comprising 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, and one or more pharmaceutically acceptably excipient, wherein the tablet comprises about 6.0% to about 7.0 % by weight of tenofovir alafenamide succinate.
In another embodiment, the present invention provides a tablet consisting of 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, and one or more pharmaceutically acceptably excipient, wherein the tablet has about6.0% to about 7.0 % by weight of tenofovir alafenamide succinate.
In another embodiment, the present invention provides a film coated tablet consisting of 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, and one or more pharmaceutically acceptably excipients, wherein the tablet has about6.0% to about 7.0 % by weight of tenofovir alafenamide succinate.
In another embodiment, the present invention provides a tablet comprising 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 500mg± 15 mg.
In another embodiment, the present invention provides a tablet comprising 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 450mg± 15 mg.
In another embodiment, the present invention provides a tablet consisting of 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 500mg± 15 mg.
In another embodiment, the present invention provides a film coated tablet consisting of 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 500mg± 15 mg.
In another embodiment, the present invention provides a tablet consisting of 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 450mg± 15 mg.
In another embodiment, the present invention provides a film coated tablet consisting of 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, wherein the tablet has a total weight of 450mg± 15 mg.
In an embodiment, the present invention provides a tablet comprising 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine and one or more pharmaceutically acceptable excipient, wherein the tablet has a total weight of 500mg± 15 mg.
In an embodiment, the present invention provides a tablet comprising 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine and one or more pharmaceutically acceptable excipient, wherein the tablet has a total weight of 450mg± 15 mg.
In an embodiment, the present invention provides a tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine and one or more pharmaceutically acceptable excipient, wherein the tablet has a total weight of 500mg± 15 mg.
In an embodiment, the present invention provides a film coated tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine and pharmaceutically acceptable excipient, wherein the tablet has a total weight of 500mg± 15 mg.
In an embodiment, the present invention provides a tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine and one or more pharmaceutically acceptable excipient, wherein the tablet has a total weight of 450mg± 15 mg.
In an embodiment, the present invention provides a film coated tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine and one or more pharmaceutically acceptable excipient, wherein the tablet has a total weight of 450mg± 15 mg.
In an embodiment, the present invention provides a tablet comprising 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine,and one or more pharmaceutically acceptable excipient selected from solubilizer, glidant, filler, binder, lubricant, diluent, preservative, surface active agent, basifying agent and dispersing agent, wherein the tablet has a total weight of 500mg± 15 mg.
In an embodiment, the present invention provides a tablet comprising 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine,and one or more pharmaceutically acceptable excipient selected fromsolubilizer, glidant, filler, binder, lubricant, diluent, preservative, surface active agent, basifying agent, dispersing agent, wherein the tablet has a total weight of 450mg± 15 mg.
In an embodiment, the present invention provides a tablet comprising 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, microcrystalline cellulose, croscarmellose, sodium stearyl fumarate, magnesium stearate, lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In an embodiment, the present invention provides a tablet comprising 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, microcrystalline cellulose, croscarmellose, sodium stearyl fumarate, magnesium stearate, lactose,wherein the tablet has a total weight of 450mg± 15 mg.
In an embodiment, the present invention provides a tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, microcrystalline cellulose, croscarmellose, sodium stearyl fumarate, magnesium stearate, lactose,wherein the tablet has a total weight of 500mg± 15 mg.
In an embodiment, the present invention provides a film coated tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, microcrystalline cellulose, croscarmellose, sodium stearyl fumarate, magnesium stearate, lactose,wherein the tablet has a total weight of 500mg± 15 mg.
In an embodiment, the present invention provides a tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, microcrystalline cellulose, croscarmellose, sodium stearyl fumarate, magnesium stearate, lactose,wherein the tablet has a total weight of 450mg± 15 mg.
In an embodiment, the present invention provides a film coated tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, microcrystalline cellulose, croscarmellose, sodium stearyl fumarate, magnesium stearate, lactose,wherein the tablet has a total weight of 450mg± 15 mg.
In an embodiment, the present invention provides a tablet comprising 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 40-50% microcrystalline cellulose, about 4-5% croscarmellose, about 1-2% sodium stearyl fumarate, about 0.1-1.0% magnesiumstearate, about 7-10% lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In an embodiment, the present invention provides a tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 40-50% microcrystalline cellulose, about 4-5% croscarmellose, about 1-2% sodium stearyl fumarate, about 0.1-1.0% magnesiumstearate, about 7-10% lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In an embodiment, the present invention provides a film coated tablet consisting of 12 to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 40-50% microcrystalline cellulose, about 4-5% croscarmellose, about 1-2% sodium stearyl fumarate, about 0.1-1.0% magnesiumstearate, about 7-10% lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In a specific embodiment, the present invention provides a tablet comprising 12.5 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, about 40-50% microcrystalline cellulose, about 4-5% croscarmellose, about 1-2% sodium stearyl fumarate, about 0.1-1.0% of magnesium stearate, about 7-10% lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In a specific embodiment, the present invention provides a tablet consisting of 12.5 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, about 40-50% microcrystalline cellulose, about 4-5% croscarmellose, about 1-2% sodium stearyl fumarate, about 0.1-1.0% of magnesium stearate, about 7-10% lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In a specific embodiment, the present invention provides a film coated tablet consisting of 12.5 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, about 40-50% microcrystalline cellulose, about 4-5% croscarmellose, about 1-2% sodium stearyl fumarate, about 0.1-1.0% of magnesium stearate, about 7-10% lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In another embodiment, the present invention provides a tablet comprising of 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, about 40-50% of microcrystalline cellulose, about 4-5% croscarmellose, about 1-2% sodium stearyl fumarate, about 0.1-1.0% magnesium stearate, about 7-10% lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In another embodiment, the present invention provides a tablet comprising of 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, about 40-50% of microcrystalline cellulose, about 4-5% croscarmellose, about 1-2% sodium stearyl fumarate, about 0.1-1.0% magnesium stearate, about 7-10% lactose, wherein the tablet has a total weight of 450mg± 15 mg.
In another embodiment, the present invention provides a tablet consisting of 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, about 40-50% of microcrystalline cellulose, about 4-5% croscarmellose, about 1-2% sodium stearyl fumarate, about 0.1-1.0% magnesium stearate, about 7-10% lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In another embodiment, the present invention provides a film coated tablet consisting of 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, about 40-50% of microcrystalline cellulose, about 4-5% croscarmellose, about 1-2% sodium stearyl fumarate, about 0.1-1.0% magnesium stearate, about 7-10% lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In another embodiment, the present invention provides a tablet consisting of 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, about 40-50% of microcrystalline cellulose, about 4-5% croscarmellose, about 1-2% sodium stearyl fumarate, about 0.1-1.0% magnesium stearate, about 7-10% lactose, wherein the tablet has a total weight of 450mg± 15 mg.
In another embodiment, the present invention provides a film coated tablet consisting of 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine, about 40-50% of microcrystalline cellulose, about 4-5% croscarmellose, about 1-2% sodium stearyl fumarate, about 0.1-1.0% magnesium stearate, about 7-10% lactose, wherein the tablet has a total weight of 450mg± 15 mg.
In a specific embodiment, the present invention provides a tablet comprising 12.5 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 225mg microcrystalline cellulose, about 20 mg croscarmellose, about 8 mg sodium stearyl fumarate, about 1 mg magnesium stearate, about 36 mg lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In a specific embodiment, the present invention provides a tablet comprising 12.5 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 225mg microcrystalline cellulose, about 20 mg croscarmellose, about 8 mg sodium stearyl fumarate, about 1 mg magnesium stearate, about 36 mg lactose, wherein the tablet has a total weight of 450mg± 15 mg.
In a specific embodiment, the present invention provides a tablet consisting of 12.5 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 225mg microcrystalline cellulose, about 20 mg croscarmellose, about 8 mg sodium stearyl fumarate, about 1 mg magnesium stearate, about 36 mg lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In a specific embodiment, the present invention provides a film coated tablet consisting of 12.5 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 225mg microcrystalline cellulose, about 20 mg croscarmellose, about 8 mg sodium stearyl fumarate, about 1 mg magnesium stearate, about 36 mg lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In a specific embodiment, the present invention provides a tablet consisting of 12.5 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 225mg microcrystalline cellulose, about 20 mg croscarmellose, about 8 mg sodium stearyl fumarate, about 1 mg magnesium stearate, about 36 mg lactose, wherein the tablet has a total weight of 450mg± 15 mg.
In a specific embodiment, the present invention provides a film coated tablet consisting of 12.5 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 225mg microcrystalline cellulose, about 20 mg croscarmellose, about 8 mg sodium stearyl fumarate, about 1 mg magnesium stearate, about 36 mg lactose, wherein the tablet has a total weight of 450mg± 15 mg.
In a specific embodiment, the present invention provides a tablet comprising 31.2 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 205 mg microcrystalline cellulose, about 20 mg croscarmellose, about 10mg sodium stearyl fumarate, about 1mg of magnesium stearate, about 36 mg lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In a specific embodiment, the present invention provides a tablet comprising 31.2 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 205 mg microcrystalline cellulose, about 20 mg croscarmellose, about 10mg sodium stearyl fumarate, about 1mg of magnesium stearate, about 36 mg lactose, wherein the tablet has a total weight of 450mg± 15 mg.
In a specific embodiment, the present invention provides a tablet consisting of 31.2 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 205 mg microcrystalline cellulose, about 20 mg croscarmellose, about 10mg sodium stearyl fumarate, about 1mg of magnesium stearate, about 36 mg lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In a specific embodiment, the present invention provides a film coated tablet consisting of 31.2 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 205 mg microcrystalline cellulose, about 20 mg croscarmellose, about 10mg sodium stearyl fumarate, about 1mg of magnesium stearate, about 36 mg lactose, wherein the tablet has a total weight of 500mg± 15 mg.
In a specific embodiment, the present invention provides a tablet consisting of 31.2 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 205 mg microcrystalline cellulose, about 20 mg croscarmellose, about 10mg sodium stearyl fumarate, about 1mg of magnesium stearate, about 36 mg lactose, wherein the tablet has a total weight of 450mg± 15 mg.
In a specific embodiment, the present invention provides a film coated tablet consisting of 31.2 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 205 mg microcrystalline cellulose, about 20 mg croscarmellose, about 10mg sodium stearyl fumarate, about 1mg of magnesium stearate, about 36 mg lactose, wherein the tablet has a total weight of 450mg± 15 mg.
In one embodiment, the present invention provides an oral pharmaceutical composition comprising (a) rilpivirine hydrochloride, (b) tenofovir alafenamide succinate and (c) emtricitabine.
In certain embodiment, the present invention provides an oral pharmaceutical composition comprising (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine,and one or more pharmaceutically acceptably excipients.
In certain embodiment, the present invention providesan oral pharmaceutical composition consisting of (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, and one or more pharmaceutically acceptably excipients.
In another embodiment, the present invention providesan oral pharmaceutical compositioncomprising (a) 27.5 mg rilpivirine hydrochloride (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, and one or more pharmaceutically acceptably excipients.
In another embodiment, the present invention providesan oral pharmaceutical composition consisting of (a) 27.5 mg rilpivirine hydrochloride (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, and one or more pharmaceutically acceptably excipients.
In certain embodiment, the present invention providesa tablet comprising (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, and one or more pharmaceutically acceptably excipients, wherein the tablet comprises about 2.0-7.0 % by weight tenofovir alafenamide succinate.
In certain embodiment, the present invention providesatablet consisting of (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, and one or more pharmaceutically acceptably excipients , wherein the tablethas about 2.0-7.0 % by weight tenofovir alafenamide succinate.
In certain embodiment, the present invention provides a film coated tablet consisting of (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, and one or more pharmaceutically acceptably excipients,wherein the tablethas about 2.0-7.0 % by weight tenofovir alafenamide succinate.
In certain embodiment, the present invention providesa tablet comprising (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, wherein the tablet has a total weight of 650mg± 25 mg.
In certain embodiment, the present invention provides a tabletconsisting of (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, wherein the tablet has a total weight of 650mg± 25 mg.
In certain embodiment, the present invention providesa film coated tablet consisting of (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, wherein the tablet has a total weight of 650mg± 25 mg.
In one embodiment, the present invention provides a film coated tablet consisting of (a) rilpivirine hydrochloride, (b) tenofovir alafenamide succinate and (c) emtricitabine, and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention provides atablet comprising(a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a tablet consisting of (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a film coated tablet consisting of (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a tablet comprising (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, microcrystalline cellulose, croscarmellose, sodium stearyl fumarate, magnesium stearate, lactose, povidone and polysorbate 20.
In another embodiment, the present invention provides a tablet consisting of (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, microcrystalline cellulose, croscarmellose, sodium stearyl fumarate, magnesium stearate, lactose, povidone and polysorbate 20.
In another embodiment, the present invention provides a film coated tablet consisting of (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, microcrystalline cellulose, croscarmellose, sodium stearyl fumarate, magnesium stearate, lactose, povidone and polysorbate 20.
In another embodiment, the present invention provides a tablet comprising (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, microcrystalline cellulose, croscarmellose, sodium stearyl fumarate, magnesium stearate, lactose, povidone and polysorbate 20, wherein the tablet has a total weight of 650mg± 25 mg.
In another embodiment, the present invention provides a tablet consisting of (a) 27.5 mg rilpivirine hydrochloride , (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, microcrystalline cellulose, croscarmellose, sodium stearyl fumarate, magnesium stearate, lactose, povidone and polysorbate 20, wherein the tablet has a total weight of 650mg± 25 mg.
In another embodiment, the present invention provides a film coated tablet consisting of (a) 27.5 mg rilpivirine hydrochloride , (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, microcrystalline cellulose, croscarmellose, sodium stearyl fumarate, magnesium stearate, lactose, povidone and polysorbate 20, wherein the tablet has a total weight of 650mg± 25 mg.
In another embodiment, the present invention provides a tablet comprising (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, about 20-25% microcrystalline cellulose, about 3-5% croscarmellose, about 0.1-1.0% sodium stearyl fumarate, about 1.0-2.0% magnesium stearate, about 20-35% lactose, about 1-2% povidone and about 0.01-1% polysorbate 20, wherein the tablet has a total weight of 650mg± 25 mg.
In another embodiment, the present invention provides a tablet consisting of (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, about 20-25% microcrystalline cellulose, about 3-5% croscarmellose, about 0.1-1.0% sodium stearyl fumarate, about 1.0-2.0% magnesium stearate, about 20-35% lactose, about 1-2% povidone and about 0.01-1% polysorbate 20, wherein the tablet has a total weight of 650mg± 25 mg.
In another embodiment, the present invention provides a film coated tablet consisting of (a) 27.5 mg rilpivirine, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, about 20-25% microcrystalline cellulose, about 3-5% croscarmellose, about 0.1-1.0% sodium stearyl fumarate, about 1.0-2.0% magnesium stearate, about 20-35% lactose, about 1-2% povidone and about 0.01-1% polysorbate 20, wherein the tablet has a total weight of 650mg± 25 mg.
In a specific embodiment, the present invention provides a tablet comprising (a) 27.5 mg rilpivirine hydrochloride , (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, about 23% microcrystalline cellulose, about 5% croscarmellose, about 0.4 % sodium stearyl fumarate, about 2.0% magnesium stearate, about 30 % lactose, about 1 % povidone and about 0.03 % polysorbate 20, wherein the tablet has a total weightof 650mg± 25 mg.
In a specific embodiment, the present invention provides a tablet consisting of (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, about 23% microcrystalline cellulose, about 5% croscarmellose, about 0.4 % sodium stearyl fumarate, about 2.0% magnesium stearate, about 30 % lactose, about 1 % povidone and about 0.03 % polysorbate 20, wherein the tablet has a total weightof 650mg± 25 mg.
In a specific embodiment, the present invention provides a film coated tablet consisting of (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, about 23% microcrystalline cellulose, about 5% croscarmellose, about 0.4 % sodium stearyl fumarate, about 2.0% magnesium stearate, about 30 % lactose, about 1 % povidone and about 0.03 % polysorbate 20, wherein the tablet has a total weightof 650mg± 25 mg.
In an embodiment, the present invention provides a tablet comprising (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, about 140 mg microcrystalline cellulose, about 30 mg croscarmellose, about 2.5 mg sodium stearyl fumarate, about 10 mg magnesium stearate, about 190 mg lactose, about 7 mg povidone and about 0.2 mg polysorbate 20, wherein the tablet has a total weightof 650mg± 25 mg.
In more specific embodiment, the present invention provides a tablet consisting of (a) 27.5 mg rilpivirine hydrochloride , (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, about 140 mg microcrystalline cellulose, about 30 mg croscarmellose, about 2.5 mg sodium stearyl fumarate, about 10 mg magnesium stearate, about 190 mg lactose, about 7 mg povidone and about 0.2 mg polysorbate 20, wherein the tablet has a total weightof 650mg± 25 mg.
In more specific embodiment, the present invention provides a film coated tablet consisting of (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, about 140 mg microcrystalline cellulose, about 30 mg croscarmellose, about 2.5 mg sodium stearyl fumarate, about 10 mg magnesium stearate, about 190 mg lactose, about 7 mg povidone and about 0.2 mg polysorbate 20, wherein the tablet has a total weight of 650mg± 25 mg.
In another embodiment, the present invention provides a multilayer tablet comprising (a) rilpivirine hydrochloride, (b) tenofovir alafenamide succinate and (c) emtricitabine, and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a multilayer tablet consisting of (a) rilpivirine hydrochloride, (b) tenofovir alafenamide succinate and (c) emtricitabine., and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a film coated multilayer tablet consisting of (a) rilpivirine hydrochloride, (b) tenofovir alafenamide succinate and (c) emtricitabine., and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a multilayer tablet comprising (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a multilayer tablet consisting of (a) 27.5 mg rilpivirine hydrochloride (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, and one or more pharmaceutically acceptable excipients
In another embodiment, the present invention provides a multilayer film coated tablet consisting of (a) 27.5 mg rilpivirine hydrochloride(b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine, and one or more pharmaceutically acceptable excipients
In another embodiment, the present invention provides a multilayer tablet comprising (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine wherein the tablet has a total weight of 650mg± 25 mg.
In another embodiment, the present invention provides a multilayer tablet consisting of (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine wherein the tablet has a total weight of 650mg± 25 mg
In another embodiment, the present invention provides a multilayer film coated tablet consisting of (a) 27.5 mg rilpivirine hydrochloride, (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine wherein the tablet has a total weight of 650mg± 25 mg
In another embodiment, the present invention provides a multilayer tablet comprising first layer of (a) 27.5 mg rilpivirine hydrochloride, and second layer of (b) about 32 mg of tenofovir alafenamide succinate equivalent to 25 mg of tenofovir alafenamide and (c) 200 mg of emtricitabine,and one or more pharmaceutically acceptable excipients
The first layer may contain rilpivirine, lactose and croscarmellose, thesecond layer may contain tenofovir alafenamide succinate, emtricitabine, microcrystalline cellulose, croscarmellose, magnesium stearate, sodium stearyl fumarate. The extra granular layers may contain microcrystalline cellulose, croscarmellose sodium, lactose, magnesium stearate, sodium stearyl fumarate and binder such as povidone and polysorbate 20.
In one embodiment, the present invention provides an oral pharmaceutical compositioncomprising (a) tenofovir alafenamide succinate, (b)cobicistat, (c) darunavir and (d) emtricitabine, and one or more pharmaceutically acceptable excipients
In one embodiment, the present invention provides an oral pharmaceutical compositionconsisting of(a) tenofovir alafenamide succinate, (b)cobicistat, (c) darunavir and (d) emtricitabine., and one or more pharmaceutically acceptable excipients
In certain embodiment, the present invention provides an oral pharmaceutical compositioncomprising (a) about 12.5 mg of tenofovir alafenamide succinate equivalent to 10 mg of tenofovir alafenamide, (b) 150 mg cobicistat, (c)800 mg darunavir and (d)200 mg emtricitabine, and one or more pharmaceutically acceptable excipients
In certain embodiment, the present invention provides an oral pharmaceutical compositionconsisting of (a) about 12.5 mg of tenofovir alafenamide succinate equivalent to 10 mg of tenofovir alafenamide, (b) 150 mg cobicistat, (c)800 mg darunavir and (d)200 mg emtricitabine, and one or more pharmaceutically acceptable excipients
In certain embodiment, the present invention provides a solid oral dosage form comprising (a) about 12.5 mg of tenofovir alafenamide succinate equivalent to 10 mg of tenofovir alafenamide, (b) 150 mg cobicistat, (c)800 mg darunavir, (d)200 mg emtricitabine and one or morepharmaceutically acceptable excipients
In certain embodiment, the present invention provides a solid oral dosage formconsisting of (a) about 12.5 mg of tenofovir alafenamide succinate equivalent to 10 mg of tenofovir alafenamide, (b) 150 mg cobicistat, (c)800 mg darunavir, (d)200 mg emtricitabine and one or more pharmaceutically acceptable excipients.

Stability Studies
The present invention has demonstrated that it is possible to formulate stable compositions containing tenofovir alafenamide succinate. It is known in art that tenofovir alafenamide deteriorates in the presence of other components/drugs/excipients. The present inventions provide stable compositions of tenofovir alafenamide succinate wherein the formulation is optimized to control all the known degradation products of tenofovir alafenamide such as PMPA, PMPA anhydride, Monophenyl PMPA, PMPA monoamide and Phenol. The degradation impurities of tenofovir alafenamide as well as other components like emtricitabine and rilpivirine is well controlled as per ICH guidelines.

The present invention also demonstrates that stability of tenofovir alafenamide succinate does not depend on the total weight of the composition. The present inventors have successfully prepared tenofovir alafenamide succinate compositions with high total tablet weight. Tablets with total weight of more than 450 mg, more than 500 mg, more than 650 mg, more than 700 mg, are all found to be stable.The comparativestability data for various formulations of the inventions are provided below, along with the stability data of other tenofovir alafenamide formulations reported in the art. The following examples illustrate the invention and they do not any way limit the scope of the invention.

Examples1: Tablet tenofovir alafenamide succinate/emtricitabine.
Component Tablet A (200/10 mg)
Qty mg Tablet B (200/25 mg)
Qty mg
Emtricitabine 200 200
Tenofovir alafenamide Succinate 12.4 31.19
Microcrystalline cellulose, 79.12 60.4
Croscarmellose sodium 15.0 15.0
Sodium Stearyl Fumarate 2.5 2.5
Magnesium Stearate 0.9 0.9
Anhydrous Lactose 36.0 36.0
Microcrystalline Cellulose 143.0 143.0
Croscarmellose sodium 5.0 5.0
Sodium Stearyl Fumarate 6.0 6.0
Total weight of Core Tablet 500 500
Film Coating
Opadry TF Yellow 15 15
Total weight of Tablet 515 515

Procedure:
Tenofovir alafenamide succinate, emtricitabine,microcrystallinecellulose,croscarmellose sodium were blendedand lubricated with magnesium stearate and sodium stearyl fumarate. The material was subjected to dry granulation with anhydrous lactose, microcrystalline cellulose and croscarmellose sodium.Sodiumstearyl fumarate was added and followed by compression and film coating.

Stability Data:
Tablet A was established at 40°C/75%RH. The below table provides comparative data to 200/10 mg emtricitabine/ tenofovir alafenamide hemi-fumarate tablet (as reported in example 4 of WO 2017004244).
Tenofovir alafenamide degradation products Tablet A Tenofovir alafenamide hemi-fumarate (2.49%)
Initial 1M 3M Initial 1M 3M
PMPA 0.16 0.14 0.28 0.22 0.60 1.32
PMPA anhydride BDL BDL 0.04 0.29 0.43 1.21
Monophenyl PMPA BDL BDL BDL ND 0.06 0.07
PMPA monoamide 0.06 0.05 0.1 0.08 0.11 0.14
Phenol 0.09 0.09 0.08 ND ND 0.07
Total degradation Tenofovir alafenamide 0.37 0.41 0.7 0.6 1.3 3.0
*ND-not detected, BDL-below detection limit (content <0.05%)

Stability Data:
Tablet B was established at 40°C/75%RH. The below table provides comparative data to 200/10 mg emtricitabine/ tenofovir alafenamide hemi-fumarate tablet (as reported in example 4 of WO 2017004244).
Tenofovir alafenamide degradation products Tablet B Tenofovir alafenamide hemi-fumarate (6.23%)
Initial 1M 3M Initial 1M 3M
PMPA 0.09 0.31 0.16 0.23 0.49 1.00
PMPA anhydride BDL 0.09 0.09 0.28 0.37 0.85
Monophenyl PMPA BDL 0.04 BDL 0.06 0.05 0.07
PMPA monoamide BDL BDL 0.05 0.06 0.08 0.11
Phenol 0.12 0.15 0.15 <0.05% 0.07
Total degradation Tenofovir alafenamide 0.27 0.79 0.56 0.6 1.0 2.2
*ND-not detected, BDL-below detection limit (content <0.05%).
Example 2 (Tablet C):Bilayer tablet, rilpivirine hydrochloride/ tenofovir alafenamide succinate/emtricitabine-
Ingredient Quantity mg
First Layer
Rilpivirine Hydrochloride 27.500
Lactose Monohydrate 152.730
Croscarmellose sodium 2.470
Povidone K30/32 7.125
Polysorbate 20 0.175
Purified water QS
Silicified Microcrystalline cellulose 81.250
Croscarmellose sodium 4.875
Ferric Oxide Yellow 0.400
Anhydrous Lactose 44.735
Magnesium Stearate 3.900
Second layer
Emtricitabine 200.000
Tenofovir Alafenamide
Succinate 31.194
Microcrystalline cellulose 52.406
Croscarmellose sodium 23.000
Magnesium Stearate 0.900
Sodium stearyl fumarate 2.500
Croscarmellose sodium 11.100
Sodium stearyl fumarate 3.900
Total weight of Core Tablet 650.000
Film Coating
Opadry TF yellow 19.500
Total weight of Tablet 669.5

Procedure: First layer: Mixing rilpivirine hydrochloride, lactose monohydrate, croscarmellose sodium, were subjected to wet granulation using povidone, polysorbate 20 and water. Dried and blended with anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and lubricated with magnesium stearate. Second layer:Tenofovir alafenamide succinate, emtricitabine,microcrystalline cellulose, croscarmellose sodiumwere blended and the lubricated with magnesium stearate and sodium stearyl fumarate. Subjected to dry granulation and mixed with croscarmellose sodium andsodium stearyl fumarate. Both layers were compressed, and film coated.

Stability Data:
Tablet C was established at 40°C/75%RH. The below table provides comparative data to 200/25/25 mg, emtricitabine/rilpivirine hydrochloride/tenofovir alafenamide fixed-dose combination tablet (as reported in example 13 of WO 2017004244).
Tenofovir alafenamide degradation products Tablet C 200/25/25 mg, emtricitabine/rilpivirine hydrochloride/tenofovir alafenamide
Initial 1M 3M Initial 1M 3M
Water content 2.3 2.62 2.14 2.9 2.3 2.3
PMPA 0.11 0.17 0.22 0.24 0.35 0.57
PMPA anhydride ND ND 0.11 <0.10 0.13 0.57
Monophenyl PMPA BDL BDL BDL <0.10% <0.10% <0.10%
PMPA monoamide 0.04 BDL 0.04 <0.10% <0.10% <0.10%
Phenol BDL BDL 0.14 0.24 0.21 0.23
Total degradation Tenofovir alafenamide 0.27 0.35 0.57 0.5 0.7 1.1
Total degradation
emtricitabine 0.06 0.06 0.06 0.0 0.0 0.0
Total degradation
rilpivirine ND ND ND 0.0 0.0 0.0
*ND-not detected, BDL-below detection limit (content <0.05%)

Example 3 (Tablet D): tablet, rilpivirine hydrochloride/ tenofovir alafenamide succinate/emtricitabine-.
Ingredients Quantity mg
Emtricitabine 200.000
Tenofovir Alafenamide
Succinate 31.194
Microcrystalline cellulose 52.406
Croscarmellose sodium 23.000
Magnesium Stearate 0.900
Sodium stearyl fumarate 2.500
Rilpivirine Hydrochloride 27.500
Lactose Monohydrate 152.730
Croscarmellose sodium 2.470
Povidone K30/32 7.125
Polysorbate 20 0.175
Purified water QS
Microcrystalline cellulose 90.200
Croscarmellose sodium 6.500
Anhydrous Lactose 45.500
Magnesium Stearate 7.800
Core Tablet weight 650.000
Film Coating
Opadry TF yellow 19.500
Total weight of Tablet 669.5

Procedure: Rilpivirine hydrochloride,lactose monohydrate,croscarmellose sodium were mixed and subjected to wet granulation usingpovidone and polysorbate in water, dried and granulated. Tenofovir alafenamide succinate, emtricitabine,microcrystallinecellulose,croscarmellose sodiumwere blended and lubricated with magnesium stearate and then subjected to dry granulation. Both granules were blended withanhydrous lactose, microcrystalline cellulose, croscarmellose sodium and lubricated with magnesium stearate followed bycompression and film coating.

Stability Data:
Tablet D was established at 40°C/75%RH and is presented in the below table:
Parameters Tablet D
Initial 1M 3M
Water content 2.3 2.38 1.92
PMPA 0.11 0.19 0.25
PMPA anhydride ND ND 0.12
Monophenyl PMPA BDL BDL BDL
PMPA monoamide BDL BDL BDL
Phenol ND ND 0.13
Total degradation Tenofovir alafenamide 0.26 0.38 0.56
Total degradation
emtricitabine 0.06 0.06 0.06
Total degradation
rilpivirine ND ND ND
*ND-not detected, BDL-below detection limit (content <0.05%)
,CLAIMS:WE CLAIMS:

1. A tablet comprising tenofovir alafenamide succinate, emtricitabine, and one or more pharmaceutically acceptable excipient.
2. The tablet of claim 1, wherein the tablet comprises 12 mg to 32 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine.
3. The tablet of claim 1, wherein the tablet comprises 12.5 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine.
4. The tablet of claim 1, wherein the tablet comprises 31.2 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine.
5. The tablet of claim 1, wherein the tablet comprises about 2.0% to about 7.0 % by weight of tenofovir alafenamide succinate.
6. The tablet of claim 1, wherein the tablet has a total weight of more than 450 mg.
7. The tablet of claim 1, wherein one or more pharmaceutically acceptable excipient is selected from solubilizer, glidant, filler, binder, lubricant, diluent, preservative, surface active agent, basifying agent and dispersing agent.
8. The tablet of claim 7, wherein solubilizer is selected from sodium lauryl sulphate, cetyltrimethylammonium bromide, polysorbates and macrogols.
9. The tablet of claim 7, wherein the lubricant is selected from magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl behenate, sodium stearyl fumarate, colloidal silicon dioxide and talc.
10. The tablet of claim 7, wherein the disintegrants is selected from starches, celluloses, cross-linked povidone, povidone, sodium starch glycolate and croscarmellose sodium.
11. The tablet of claim 7, wherein the binder is selected from cross-linked povidone, HPMC, microcrystalline cellulose, sucrose and starches.
12. The tablet of claim 2, wherein tablet comprises 12 mg to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, microcrystalline cellulose, croscarmellose, sodium stearyl fumarate, magnesium stearate and lactose.
13. The tablet of claim 12, wherein tablet comprises 12 mg to 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 40-50% microcrystalline cellulose, about 4-5% croscarmellose, about 1-2% sodium stearyl fumarate, about 0.1-1.0% magnesium stearate and about 7-10% lactose.
14. A tablet of claim 1, wherein the tablet further comprises rilpivirine hydrochloride.
15. The tablet of claim 14, wherein the tablet comprises 27.5 mg rilpivirine hydrochloride, 32 mg of tenofovir alafenamide succinate and 200 mg of emtricitabine.
16. The tablet of claim 15, wherein the tablet comprises 27.5 mg rilpivirine hydrochloride, 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, microcrystalline cellulose, croscarmellose, sodium stearyl fumarate, magnesium stearate, lactose, povidone and polysorbate 20.
17. The tablet of claim 16, wherein the tablet comprises 27.5 mg rilpivirine hydrochloride, 32 mg of tenofovir alafenamide succinate, 200 mg of emtricitabine, about 20-25% microcrystalline cellulose, about 3-5% croscarmellose, about 0.1-1.0% sodium stearyl fumarate, about 1.0-2.0% magnesium stearate, about 20-35% lactose, about 1-2% povidone and about 0.01-1% polysorbate 20.