OA17316A

OA17316A - Therapeutic compositions comprising Rilpivirine HCL and Tenofovir Disoproxil Fumarate.

Info

Publication number: OA17316A
Application number: OA1201300212
Authority: OA
Inventors: Reza Oliyai; Lauren Wiser; Mark Menning
Original assignee: Gilead Sciences, Inc.; Janssen R & D Ireland
Priority date: 2010-11-19
Filing date: 2011-11-18
Publication date: 2016-05-23

Abstract

The invention provides multilayer tablets that contain rilpivirine hydrochloride, emtricitabine, and tenofivir disoproxil fumarate. The tablets are useful for the treatment of HIV.

Description

THERAPEUTIC COMPOSITIONS

Priorityof Invention

This application claims priority to United States Provisional Application Number 61/415,600 that was filed on 19 November 2010. The entire content ofthis provisional application is hereby incorporated herein by reference.

Background of the Invention

Rilpivirine HCl (RPV), an investigational new drug for the treatment of HIV infection, has the following formula I:

It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRT1) with longer half-life and better side-effect profile compared with other commercial NNRTIs, inciuding efavirenz.

Emtricitabine (FTC) is a nucleoside reverse transcriptase inhibitor having the following formula II:

Emtricitabine is présent as an active ingrédient in EMTRIVA® (emtricitabine) capsules, TRUVADA® (emtricitabine and tenofovir DF) tablets, and ATRIPLA® (efavirenz, emtricitabine, and tenofovir DF) tablets, which are marketed for the treatment of HIV infection.

. 4 λ

* *

Tenofovir disoproxil fumarate (Tenofonr DF or TDF) is a reverse transcriptase inhibitor having the following formula III:

HO₂C

IU

Tenofovir DF is also présent as an active ingrédient in VIREAD® (tenofovir DF) tablets, TRUVADA® (emtricitabine and tenofovir DF) tablets, and ATRIPLA® (efavirenz, emtricitabine, and tenofovir DF) tablets.

A combination of rilpivirine HCl, emtricitabine, and tenofovir DF is currently being investigated in clinical studies for the treatment of HIV (for example TMC278-TÎDP6-C209: A Clinical Trial in Treatment Naïve HIV-l Patients Comparing TMC27S to Efavirenz in Combination With Tenofovir + Emtricitabine at www.clinicaltrials.gov/ct2/show/NCT00540449?term=TMC278&rank=l0. In the current clinical studies this combination is administered as two tablets: one tablet containing rilpivirine HCl, and the second tablet being the commercial product TRUVADA® (emtricitabine 200 mg / tenofovir DF 300 mg).

A fixed-dose combination product containing rilpivirine HCl, emtricitabine, and tenofovir DF in a solid oral dosage form would be désirable. Such a fixed-dose combination would provide patient dosing convenience for once daily administration. Clinical studies hâve demonstrated high levels of compliance and treatment satisfaction, with simple once-daily highly active antirétroviral thérapies (HAART), resulting in durable suppression of HIV-l RNA.

International patent application publication number WO 2005/021001 discusses a co-wet granulation process for preparing a single tablet that comprises rilpivirine HCl, emtricitabine, and tenofovir DF. Unfortunately chemical stability of tenofovir DF is affected in the presence of rilpivirine HCI. Thus, the formulation provided by the co-wet granulation process discussed in WO 2005/021001 is not idéal for human clinical use.

There is currently a need for a fixed-dose combination product containing rilpivirine HCl, emtricitabine, and tenofovir DF. Ideally, the fixed-dose combination product will provide suitabie chemical stability for the active ingrédients and will be of an acceptable size as a unit »

. * dose form. Additîonally, it would be bénéficiai for the fixed-dose form to produce human plasma concentrations of each of the three agents that are équivalent to the plasma concentrations produced by the administration of the individual agents.

Summary of the Invention

Applicant has discovered a single multîlayer formulation of rilpivirine HCI, emtricitabine, and tenofovir DF that provides suitable chemical stability for the active ingrédients as well as plasma concentrations of the three agents that are équivalent to the plasma concentrations produced by the administration of Emtriva (emtricitibine 200 mg) capsules, Viread (tenofovir DF 300 mg) tablets, and a third tablet containing rilpivirine HCl that is currently being evaluated in clinical trials. Additîonally, the single multîlayer formulations identified by Applicant provide a similar drug exposure, as measured by the plasma concentration area under the curve (AUC), when dosed with and without food as compared to the dosing ofthe individual components with food. Dosing the individual components without food showed a decrease in rilpivirine exposure (AUC) by 21% compared to dosing the individual components with food. Having a restriction of dosing with food only can complicate the dosing regimen and compromise patient dosing compliance.

Accordingly, in one embodiment the invention provides a tablet comprising a first layer and a second layer wherein; a) the first layer comprises rilpivirine HCl; b) the second layer comprises tenofovir DF; and c) the tablet further comprises emtricitabine.

In one embodiment the invention provides a method for treating HIV infection in a human comprising administering to the human a tablet of the invention, wherein rilpivirine AUC aehieved following administration to the human when fed is no more than about 25% greater than rilpivirine AUC aehieved when administered to the human when fasted.

In one embodiment the invention provides a method for treating HIV infection in a human comprising administering to the human a tablet of the invention, wherein rilpivirine Cmax aehieved following administration to the human when fed is no more than about 25% greater than rilpivirine Cmax aehieved when administered to the human when fasted.

in one embodiment the invention provides a tablet of the invention for use in the prophylactic or therapeutic treatment of an HIV infection, wherein rilpivirine AUC aehieved following administration to the human when fed is no more than about 25% greater than rilpivirine AUC aehieved when administered to the human when fasted.

In one embodiment the invention provides a tablet of the invention for use in the prophylactic or therapeutic treatment of an HIV infection, wherein rilpivirine C_m„ aehieved « ‘ » following administration to the human when fed is no more than about 25?ô greater than rilpivirine C_max achieved when administered to the human when fasted.

!n one embodiment the invention provides a tablet of the invention for use in the prophylactic or therapeutic treatment of an HIV infection.

In one embodiment the invention provides the use of a tablet as described in any one of claims l -32 for preparing a médicament for treating HIV infection in a human.

The invention also provides processes described herein for preparing tablets of the invention as well as novel intermediate mixtures that are usefiil for preparing tablets of the 10 invention.

The tablets of the invention represent an advance in the development of multi-drug therapy for the treatment of viral infections such as HIV.

Brief Description of the Figures

FIG. I. Illustrâtes a tablet of the invention.

FIG. 2. Illustrâtes a tablet of the invention.

FIG. 3. Illustrâtes a tablet of the invention.

FIG. 4. Is a flow diagram that illustrâtes the préparation of a représentative tablet of the invention that is described in Example l.

FIG. 5. Is a flow diagram that illustrâtes the préparation of a représentative tablet of the 20 invention that is described in Example 2.

FIG. 6. Is a flow diagram that illustrâtes the préparation of a représentative tablet of the invention that is described in Example 3.

FIG. 7. Illustrâtes the percent total TDF dégradation over time measured in Comparative Example l.

FIG. 8. Illustrâtes the percent total TDF dégradation over time measured in Comparative

Example 4.

FIG. 9. Illustrâtes the percent RPV dissolved as measured in Example 5.

Detailed Description

As used herein with respect to the methods of the invention, administration to a human when “fed” means administering a tablet of the invention to a human within 5 minutes of the human consuming a standardized meal of about 300 to 600 calories and about 10 to about 15 grams of fat.

A *

As used herein with respect to the methods of the intention, administration to a human when “fasted” includes administering a tablet of the invention to a human who has not consumed food in the time period from about 8 hours prior to administration of the tablet to about 4 hours after administration of the tablet.

As used herein, when a tablet of the invention comprises a layer that is “substantially free” of a given component it means that less than 5% of the total weight of the given component présent in the tablet is found in that layer. In one embodiment of the invention when a tablet of the invention comprises a layer that is “substantially free” of a given component it means that less than l % of the total weight of the given component présent in the tablet is found in that layer.

Spécifie values listed below for ranges and terms are for illustration only, they do not exclude other values.

In one embodiment the invention provides a tablet wherein the second layer comprises the emtricitabine.

In one embodiment the invention provides a tablet which comprises 27.5 ± l .4 mg of rilpivirine HCl.

In one embodiment the invention provides a tablet which comprises 200 ± 10.0 mg of emtricitabine.

In one embodiment the invention provides a tablet which comprises 300 ± 15.0 mg of tenofovir DF.

In one embodiment of the invention the first layer further comprises one or more diluents, disintegrants, binders, or lubricants.

In one embodiment of the invention the total weight of the first layer in the tablet of the invention is 275 ± 75 mg.

In one embodiment of the invention the total weight of the first layer in the tablet is greater than 225 mg.

In one embodiment of the invention the total weight of the first layer in the tablet of the invention is 275 ± 50 mg.

In one embodiment the invention provides a tablet of the invention wherein the first layer comprises lactose monohydrate, povidone, croscarmellose sodium, polysorbate 20, microcrystalline cellulose, and magnésium stéarate.

In one embodiment the invention provides a tablet of the invention wherein the first layer comprises a basifying agent. In one embodiment of the invention the basifying agent is selected

I * » from croscarmellose sodium, calcium carbonate, sodium hydroxide, aluminum oxide, alkali métal hydroxides (e.g. such as sodium hydroxide, potassium hydroxide and lithium hydroxide), alkaline earth métal hydroxides (e.g. calcium hydroxide, and magnésium hydroxide), aluminum hydroxide, dihydroaluminum, sodium carbonate, aluminum magnésium hydroxide sulfate, aluminum hydroxide magnésium carbonate, ammonium hydroxides, magnésium carbonate, magnésium stéarate, piperazine, sodium acetate, sodium citrate, sodium tartrate, sodium maleate, and sodium succinate and mixtures thereof.

In one embodiment the invention provides a tablet of the invention wherein the first layer comprises croscarmellose sodium, and polysorbate 20.

In one embodiment the invention provides a tablet of the invention wherein the second layer comprises microcrystalline cellulose and croscarmellose sodium.

In one embodiment the invention provides a tablet of the invention wherein the second layer comprises lactose monohydrate, pre-gelatinized starch, microcrystalline cellulose, croscarmellose sodium, and magnésium stéarate.

In one embodiment the invention provides a tablet of the invention wherein the first layer is in contact with the second layer.

In one embodiment the invention provides a tablet of the invention that further comprises a third layer that is between and that séparâtes the first layer and the second layer. In one embodiment the third layer comprises lactose monohydrate, or microcrystalline cellulose, or a mixture thereof.

In one embodiment the invention provides a tablet of the invention wherein the first layer 25 is a film coating that covers the second layer.

In one embodiment the invention provides a tablet of the invention wherein the first layer is a polymeric film coating that completely covers the second layer.

In one embodiment the invention provides a tablet that further comprises a film coating. In one embodiment the film coating comprises 34 ± 12 mg ofOpadry II Purple 33G100000.

In one embodiment the invention provides a tablet wherein at least about 5.4 weight percent of the first layer is croscarmellose sodium and at least about 63.3 weight percent of the first layer is lactose monohydrate.

. t » *

In one embodiment the invention provides a tabiet wherein less than about 12.2 weight percent of the first layer is rilpivirine hydrochloride.

In one embodiment the invention provides a tabiet wherein less than about 12 weight percent of the first layer is rilpivirine hydrochloride.

In one embodiment the invention provides a tabiet wherein the first layer comprises

27.5 ± 1.4 mg of rilpivirine hydrochloride and v> herein the total weight of the first layer is at least about 230 mg.

27.5 ± 1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 240 mg.

27.5 ±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 250 mg.

27.5 ±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 260 mg.

27.5 ±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 270 mg.

27.5 ±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 280 mg.

27.5 ± 1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 290 mg.

27.5 ±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 300 mg.

27.5 ±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 230 mg and is less than about 325 mg.

• I s

In one embodiment the invention provides a tablet wherein the first layer comprises

27.5 ±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 300 mg and is less than about 325 mg.

27.5 ± 1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 290 mg and is less than about 310 mg.

In one embodiment the invention provides a tablet prepared as described herein.

In one embodiment the invention provides a tablet of the invention wherein the first layer comprises:

Ingrédient	Unit Formula for Tablets (mg/tablet)
Rilpivirine HCl	27.5 ±1.4
Microcrystalline Cellulose	60.0 ±3
Polysorbate 20	0.4 ± 0.02
Croscarmellose Sodium	16.1 ±0.8

and the second layer comprises:

Ingrédient	Unit Formula for Tablets (mg/tablet)
Emtricitabine	200 ±10
Tenofovir DF	300 ±15
Microcrystalline Cellulose	150 ±7.5
Croscarmellose Sodium	60 ±3

• I

Ingrédient	Later (% w/w)	Total Tablet (% w/w)	Unît Formula for Tablets (mg'tablet)
Rilpivirine HCl	9.2	2.4	27.5
Microcrystalline Cellulose	20.0	5.2	60.0
Lactose Monohydrate	63.3	16.5	189.8
Povidone	l.l	0.3	3.3
Polysorbate 20	O.l	0.03	0.4
Croscarmellose Sodium	5.4	1.4	16.1
Magnésium Stéarate	1.0	0.3	3.0

and the second layer comprises:

Ingrédient	Layer (% w/w)	Total Tablet (% w/w)	Unît Formula for Tablets (mg/tablet)
Emtricitabine	23.5	17.4	200.0
Tenofovir DF	353	26.1	300.0
Microcrystalline Cellulose	17.6	13.0	150.0
Lactose Monohydrate	9.4	7.0	80.0
Pregelatinized Starch	5.9	4.3	50.0
Croscarmellose Sodium	7.1	5.2	60.0
Magnésium Stéarate	12	0.9	10.0.

In one embodiment the invention provides a tablet comprising a first layer that comprises:

Ingrédient	Layer (% w/w)	Total Tablet (% w/w)	Unît Formula for Tablets (mg/tablet)
Rilpivirine HCl	92	2.4	27.5
Microcrystalline Cellulose	20.0	52	60.0
Lactose Monohydrate	63.3	16.5	189.8
Povidone	1.1	0.3	33
Polysorbate 20	0.1	0.03	0.4
Croscarmellose Sodium	5.4	1.4	16.1
Magnésium Stéarate	1.0	0.3	3.0

a second layer that comprises:

I

ΙΟ

Ingrédient	Laser (% w/w)	Total Tablet (% w/w)	Unit Formula for Tablets (mg/tablet)
Emtricitabine	23.5	17.4	200.0
Tenofovir DF	35.3	26.1	300.0
Microcrystalline Cellulose	17.6	13.0	150.0
Lactose Monohydrate	94	7.0	SO.O
Pregelatinized Starch	5.9	4.3	50.0
Croscarmellose Sodium	7.1	5.2	60.0
Magnésium Stéarate	1.2	0.9	10.0

and a third layer that is between and that séparâtes the first layer and the second layer that comprises 150 ± 8.0 mg of microcrystalline cellulose or lactose monohydrate, or a mixture thereof.

In one embodiment the invention provides a tablet of the invention wherein the first layer consists of:

Ingrédient	Layer (% w/w)	Total Tablet (% w/w)	Unit Formula for Tablets (mg/tablet)
Rilpivirine HCl	92	2.4	27.5
Microcrystalline Cellulose	20.0	5.2	60.0
Lactose Monohydrate	633	16.5	189.8
Povidone	1.1	0.3	3.3
Polysorbate 20	0.1	003	0.4
Croscarmellose Sodium	5.4	1.4	16.1
Magnésium Stéarate	1.0	0.3	3.0

and the second layer consists of:

i

Ingrédient	Layer (% w/w)	Total Tablet (% «/h)	Unit Formula for Tablets (mg/tablet)
Emtricitabine	23.5	17.4	200.0
Tenofovir DF	35.3	26.1	300.0
Microcrystalline Cellulose	17.6	13.0	150.0
Lactose Monohydrate	9.4	7.0	80.0
Pregelatinized Starch	5.9	4.3	50.0
Croscarmellose Sodium	7.1	5.2	60.0
Magnésium Stéarate	12	0.9	10.0.

In one embodiment the invention provides a tablet comprising a first layer that consists of:

Ingrédient	Layer (% w/w)	Total Tablet (*/. w/w)	Unit Formula for Tablets (mg/tablet)
Rilpivirine HCI	9.2	2.4	27.5
Microcrystalline Cellulose	20.0	52	60.0
Lactose Monohydrate	63.3	16.5	189.8
Povidone	1.1	0.3	3.3
Polysorbate 20	0.1	003	0.4
Croscarmellose Sodium	5.4	1.4	16.1
Magnésium Stéarate	1.0	0.3	3.0

a second layer that consists of:

Ingrédient	Layer (% w/w)	Total Tablet (·/. w/w)	Unit Formula for Tablets (mg/tablet)
Emtricitabine	23.5	17.4	200.0
Tenofovir DF	35.3	26.1	300.0
Microcrystalline Cellulose	17.6	13.0	150.0
Lactose Monohydrate	9.4	7.0	80 0
Pregelatinized Starch	5.9	4.3	50 0
Croscarmellose Sodium	7.1	52	60.0
Magnésium Stéarate	12	0.9	10.0

I and a third layer that is between and that séparâtes the first laverand thesecond layer that comprises 150 ± 8.0 mg of microcrystalline cellulose or lactose monohydrate, or a mixture thereof.

In one embodiment the invention provides a tablet of the invention wherein the first layer is a film coating that covers the second layer and wherein the first layer comprises 27.5 ± 1.4 mg of rilpivirine HCl; and the second layer comprises:

Ingrédient	Layer (% w/w)	Total Tablet (% w/w)	Unit Formula for Tablets (mg/tablet)
Emtricitabine	23.5	17.4	200.0
Tenofovir DF	35.3	26.1	300.0
Microcrystalline Cellulose	17.6	13.0	150.0
Lactose Monohydrate	9.4	7.0	80.0
Pregelatinized Starch	5.9	4.3	50.0
Croscanriellose Sodium	7.1	5.2	60.0 and
Magnésium Stéarate	12	0.9	10.0.
In one embodiment the invention	provides a tabl	et of the invent	ion wherein the first layer
is a film coating that covers the second la	yer and wherei	n the first layer	comprises 27.5 ± 1.4 mg
of rilpivirine HCl; and the second layer consists of:
	Lajer	Total Tablet	Unit Formula for Tablets
Ingrédient	(% w/w)	(’/. w/w)	(mg/tablet)
Emtricitabine	23.5	17.4	200.0
Tenofovir DF	35.3	26.1	300.0
Microcrystalline Cellulose	17.6	13.0	150.0
Lactose Monohydrate	9.4	7.0	80.0
Pregelatinized Starch	5.9	4.3	50.0
Croscarmellose Sodium	7.1	52	60.0
Magnésium Stéarate	1.2	0.9	10.0.

t

Ingrédient	% w/w	Unit Formula for Tablets (mg/tablet)
Riîpivirine HCl	2.4	27.5
Microcrystalline Cellulose	5.2	60.0
Lactose Monohydrate	16.5	189.8
Povîdone	0.3	3.3
Polysorbate 20	0.03	0.4
Croscannellose Sodium	1.4	I6.l
Magnésium Stéarate	0.3	3.0

and the second layer comprises:

Ingrédient	% w/w	Unit Formula for Tablets (mg/tablet)
Emtricitabine	17.4	200.0
TenofovirDF	26.1	300.0
Microcrystalline Cellulose	13.0	150.0
Lactose Monohydrate	7.0	80.0
Pregelatinized Starch	4.3	50.0
Croscarmellose Sodium	5.2	60.0
Magnésium Stéarate	0.9	10.0.

Ingrédient	% w/w	Unit Formula for Tablets (mg/tablet)
Riîpivirine HCl	2.4	27.5
Microcrystalline Cellulose	5.2	600
Lactose Monohydrate	16.5	189.8
Povîdone	0.3	3.3
Polysorbate 20	0.03	0.4
Croscarmellose Sodium	1.4	16.1
Magnésium Stéarate	0.3	3.0

a second layer that comprises:

·

Ingrédient	% «/«'	Unît Formula for Tablets (mg/tablet)
Emtricitabîne	17.4	200.0
Tenofovir DF	26.1	300.0
Microcrystalline Cellulose	13.0	150.0
Lactose Monohydrate	7.0	80.0
Pregelatinized Stareh	4.3	50.0
Croscarmellose Sodium	5.2	60.0
Magnésium Stéarate	0.9	10.0

and a third layer that is between and that séparâtes the first layer and the second layer that comprises 150 ± 8.0 mg of microcrystalline cellulose or lactose monohydrate, or a mixture 5 thereof.

Ingrédient	% w/w	Unit Formais for Tablets (mg/tablet)
Rilpivirine HCl	2.4	27.5
Microcrystalline Cellulose	5.2	60.0
Lactose Monohydrate	16.5	189.8
Povidone	0.3	33
Polysorbate 20	0.03	0.4
Croscarmellose Sodium	1.4	16.1
Magnésium Stéarate	0.3	3.0

and the second layer consists of:

t is

Ingrédient	% w/w	Unit Formula for Tablets (mg/tablet)
Emtricitabine	17.4	200.0
Tenofovir DF	26.1	300.0
Microcrystalline Cellulose	13.0	150.0
Lactose Monohydrate	7.0	80.0
Pregelatinized Starch	4.3	50.0
Croscarmellose Sodium	5.2	60.0
Magnésium Stéarate	0.9	10.0.

Ingrédient	·/. n/w	Unit Formula for Tablets (mg/tablet)
Rilpivirine HCl	2.4	27.5
Microcrystalline Cellulose	5.2	60.0
Lactose Monohydrate	16.5	189.8
Povidone	0.3	33
Polysorbate 20	0.03	0.4
Croscarmellose Sodium	1.4	16.1
Magnésium Stéarate	0.3	3.0

a second layer that consists of:

Ingrédient	% w/w	Unit Formula for Tablets (mg/tablet)
Emtricitabine	17.4	200.0
Tenofovir DF	26.1	300.0
Microcrystalline Cellulose	13.0	150.0
Lactose Monohydrate	7.0	80.0
Pregelatinized Starch	4.3	50.0
Croscarmellose Sodium	52	60.0
Magnésium Stéarate	0.9	10 0

In one embodiment the invention provides a tablet of the invention wherein the first layer 5 is a film coating that covers the second layer and wherein the first layer comprises 27.5 ± l .4 mg of rilpivirine HCl; and the second layer comprises:

Ingrédient	% v/w	Unit Formula for Tablets (mg/tablet)
Emtricitabine	17.4	2000
Tenofovir DF	26.1	300,0
Microcrystalline Cellulose	13.0	150,0
Lactose Monohydrate	7.0	80.0
Pregelatinized Starch	4.3	50.0
Croscarmellose Sodium	5.2	60.0 and
Magnésium Stéarate	0.9	10.0.

In one embodiment the invention provides a tablet of the invention wherein the first layer is a film coating that covers the second layer and wherein the first layer comprises 27.5 ± l .4 mg of rilpivirine HCI; and the second layer consists of:

Ingrédient	% w/w	Unit Formula for Tablets (mg/tablet)
Emtricitabine	17.4	200.0
Tenofovir DF	26.1	3000
Microcrystalline Cellulose	13.0	150.0
Lactose Monohydrate	7.0	80.0
Pregelatinized Starch	4.3	50.0
Croscarmellose Sodium	5.2	60.0 and
Magnésium Stéarate	0.9	10.0.

The tablets of the invention may include one or more acceptable carriers. The carrier(s) should be acceptable in the sense of being compatible with the other ingrédients of the formulation and physiologically innocuous to the récipient thereof. As used herein the term carrier includes excipients, glidants, fillers, binders, lubricant, diluents, preservatives, surface *

active agents, dispersing agents and the like. For exampie, see the Handbook of Pharmaceutical

Excipients (APhA Publications, Washington, DC), which is hereby incorporated by référencé herein in its entirety. The term carrier also includes agents such as sweetening agents, flavoring agents, coloring agents and preserving agents. Furthermore, these terms include the values mentioned herein as well as values in accord with ordinary practice.

The tablets of the invention can also comprise a film coating that covers a portion or ail ofthe tablet. Film coatings are known in the art and can be composed ofhydrophîlic 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. Though the water soluble material included in the film coating of the présent invention may include a single polymer material, it may also be formed using a mixture of more than one polymer. In one embodiment of the invention, the film coating comprises Opadry II Purple 33G100000, which is available from Colorcon.

The tablets of the invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA), which is hereby incorporated by référencé herein in its entirety. Such methods include the step of bringing into association the active ingredient(s) with the carrier which constitutes one or more accessory ingrédients.

A tablet can be made by compression or molding, optionally with one or more accessory ingrédients. Compressed tablets may be prepared by compressing in a suitable machine the active ingrédient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, préservâtive, surface active agent or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingrédient moistened with an inert liquid diluent. The tablets may optionally be coated, for example with a polymeric film coating that can optionally comprise a compound of formula I.

Figure l shows a cross-section of a tablet (lOl) of the invention. The tablet includes a first layer (l 03) that comprises rilpivirine HCl. The tablet also includes a second layer (l 05) that comprises tenofovir DF. The first and second layer can each also further comprise emtricitabine.

Figure 2 shows a cross-section of a tablet (101) of the invention. The tablet includes a first layer (103) that comprises rilpivirine HCl. The tablet also includes a second layer (l05) that

I is comprises tenofovir DF and a third layer (l 07) that is inert. The first and second layer can each also further comprise emtricitabine.

Figure 3 shows a cross-section of a tablet (101) of the invention. The tablet includes a first layer (109) that comprises rilpivirine HCl and a second layer (l 05) that comprises tenofovir

DF and emtricitabine, wherein the first layer (!09) is a coating that covers the second layer (l05). Comparative Examnles

Comparative Example 1. Préparation and Stability Evaluation of Co-wet Granulation Formulation of FTC, RPV, and TDF

A single co-wet granulation process was used to formulate FTC, RPV, and TDF, based on the formulation composition of TRUVADA ® (emtricitibine 200 mg / tenofovir DF 300 mg) and the RPV Phase 3 clinical formulation. Because a co-wet granulation process has the benefit of ease of manufacturing it is frequently the first-choice approach to develop FDC products. The low dose of RPV and the use of excipients common in VIREAD® (tenofovir DF), TRUVADA ® (emtricitibine 200 mg / tenofovir DF 300 mg), and EMTRIVA® (emtricitibine) made

FTC/RPV/TDF amenable to a single-layer wet granulation process. One challenge was to maintain the stability of TDF in the presence of a surfactant.

The compositions and processing parameters of the co-wet granulation formulations evaluated are summarized in Table CEI .1 and CE1.2, respectively. Wet granulation was carried out in the presence and absence of non-ionic surfactants (poloxamer 188 and polysorbate 20).

Table CEI.1 % w/w

	3639- 182	3639- 183	3866- 1	3866- 2	3866- 22
Intragrannlar Ingrédients
Rilpivirine HCl	3.6	3.6	3.6	3.6	2.75
Emtricitabine	26.3	26.3	26.3	26.3	20.0
Tenofovir disoproxil fumarate	39.5	39.5	39.5	39.5	30.0
Microcrystalline cellulose, NF (102)	14.2	22.2	22.2	22.6	15.0
Polysorbate 20	0.4	0.4
Poloxamer 188			0.4
Hydroxypropyl cellulose		2.0	2.0	2.0
Croscarmellose sodium, NF	2.5	2.5	2.5	2.5	3.0

Lactose monohydrate (DCL-l 1)

5.0

Lactose monohjdrate, NF, 310 ReguIar'Grind	8.0
Pregelatinized starch, NF	5.0	50
Extragranular Ingrédients
Microcrystalline cellulose, NF (102)					12.25
Croscarmellose sodium, NF	2.5	2.5	2.5	2.5	3.0
Magnésium stéarate, NF	1.0	1.00	1.00	1.0	1.0
Total	100.0	100.0	100.0	100.0	100.0
Total tablet weight	760 mg	760 mg	760 mg	760 mg	1000 mg

Table CE 1.2

Lot Number	Batch Size (g)	Intragranular Amount (g)	Water for	Géométrie Mean Diameter Particle Size (pm)	LOD (%)
(g)	(%)	- Water Addition Time	Wet Massing
3639-182	800	772	277.5	36	8:30	1	169	0.74
3639-183	800	772	277.6	38	7:49	1	187	0.56
3866-1	800	772	275.0	36	8:27	1	226	0.49
3866-2	800	772	275.0	36	8:00	1	204	0.56
3866-22	800	670	175.0	41	5:19	0	207	0.96

The uncoated tablets were packaged with 3 g of silica gel desiccant and stored in 50°C and 40°C/75% RH stability chambers to stress the tablet samples and accelerate the dégradation rate to give an indication of longer term stability of the tablets under ambient conditions (25°C/60% RH). Preformulation studies hâve shown that TDF undergoes hydrolysis in an aqueous solution and to a smaller degree in the solid state after exposure to humidity and heat. The dégradation products axe mono-POC PMPA, isopropanol, carbon dioxide, and formaldéhyde. The rate and extent of dégradation of TDF in the co-wet granulation formulations was significantly higher than in commercial TRUVADA ® (emtricitabine 200 mg / tenofovir DF 300 mg) tablets. The total TDF-related impurities and dégradation products increased to more than 4% after 2 weeks at 50°C. Various attempts to improve the chemical stability of TDF in the co-wet granulation formulations by removing surfactant or by increasing the concentrations of microcrystalline cellulose and pregelatinized starch failed to improve formulation stability. These results demonstrate that a co-wet granulation process is not idéal for human clinical use.

The stability data at 5OC are summarized in Figure 7. Ail formulations show a much greater dégradation rate of TDF than in TRUVADA ® (emtricitabine 200 mg / tenofovir DF 300 mg) tablets.

As illustrated below in Example 6 représentative tablets of the invention overcome the problem of reduced TDF stability présent in the co-wet formulation above.

Comparative Example 2. Préparation of Formulation 1

Formulation 1 was manufactured by blending FTC, RPV, and TDF together with excipients then dry granulating them together using a dry granulation process, which employs a roller compactor and mill. The granules were blended with extragranular excipients and compressed into tablet cores, which were then film-coated. The composition parameters for the co-dry granulation formulation (Formulation 1) are summarized in Table CE2.1

Table CE2.1

Ingrédient	Unit Formula for FTC/RPV/TDF Tablets (mg/tablet)
Emtricitabine	200.0
Rilpivirine Hydrochloride	27.5*
Tenofovir Disoproxil Fumarate	300.0”
Microcrystalline Cellulose	218.4
Croscarmellose Sodium	85.0
Magnésium Stéarate	19.1
Tablet Core Weight	850.0
Film Coat Components
Opadry II Purple 33G100000	25.5
Total Tablet Weight	875.5

a b

Equivalent to 25.0 mg of rilpivirine free base

Equivalent to 245 mg of tenofovir disoproxil

I

Comparative Exemple 3. Préparation of Formulation 2

Formulation 2 was prepared using two separate granulation processes in which rilpivirine HCl was w'et granulated by a fluid-bed granulation process and emtricitabine and tenofovir DF were co-granulated in a high shear wet granulation process. This formulation was designed to use the intragranular rilpivirine HCl formulation and fluid-bed granulation process used to préparé the RPV tablet that is now being evaluated in Phase 3 clinical trials. The emtricitabine/tenofovir DF powder blend was produced using the process and the intragranular composition used in the manufacture of TRUVADA ® (emtricitibine 200 mg / tenofovir DF 300 mg). The tw'o granulations were then blended together with lubricant, compressed into a single layer tablet, and then film-coated. The composition parameters of Formulation 2 are summarized in Table CE3.1

Table CE3.1

Ingrédient	Unit Formula for FTC/RPV/TDF Tablets (mg/tablet)
Emtricitabine	200.0
Rilpivirine Hydrochloride	27.5*
Tenofovir Disoproxil Fumarate	300.0^b
Microcrystalline Cellulose	212.7
Lactose Monohydrate	135.1
Povidone	33
Pregelatintzed Starch	50.0
Polysorbate 20	0.4
Croscarmellose Sodium	61.1
Magnésium Stéarate	10.0
Tablet Core Weight	1000.0
Film Coat Components Opadry II Purple 33G100000 Total Tablet Weight	30.0 1030.0

a Equivalent to 25.0 mg rilpivirine free base, b Equivalent to 245 mg of tenofovir disoproxil

Comparative Example 4. Stability of Formulation 1 and Formulation 2

Identity and strengths of the APIs and dégradation products were determined using an

HPLC method, which employed a 4.6 x 250-mm C-12 column (4-pm particle size) for chromatographie séparation by reversed-phase chromatography using a mobile phase consisting

I

-)7 of ammonium acetate buffer and acetonitrile with gradient elution over approximately minutes. Composite samples of 10 tablets were dissolved and diluted to final concentrations of approximately 0.08 mg/mL RPV, 0.64 mg/mL FTC, and 0.96 mg/mL TDF with a4:3:3 pH 3 phosphate buffenacetonitrile:methanol solution. The strength and dégradation product content of FTC, RPV, and TDF were determined by HPLC using area normalization and extemal reference standards at a wavelength of262 nm. The stability data for 30 count tablets stored at 40°C/75% RH in induction sealed bottles containing 3 g silica gel desiccant are summarized in Figure 8.

In Comparative Example 5 below the bioavailabilitiesof Formulation 1 and Formulation 2 from Comparative Examples 2 and 3 were assessed. Formulations 1 and 2 both failed to demonstrate bioequivalence for rilpivirine with significantly higher area under the curve (AUC) and Cmax levels than those obtained with the rilpivirine tabiet that is now being evaluated in clinical trials. Accordingly, the human plasma concentration of rilpivirine produced by Formulation 1 and by Formulation 2 is not équivalent to the plasma concentration of rilpivirine produced in the current clinical trials. A représentative tabiet of the invention did demonstrate the bénéficiai property of providing a plasma concentration of rilpivirine that is équivalent to the plasma Ievel produced in the current clinical trials (See Example 5 below).

Comparative Example 5. Bioavailability of Formulation 1 and Formulation 2

A clinical study was conducted to assess the bioavailability and bioequivalence of Formulations 1 and 2 relative to co-administration of the individual components, with ail treatments administered in the fed state. Formulations 1 and 2 both failed to demonstrate bioequivalence for rilpivirine with significantly higher area under the curve (AUC) and Cmax levels than those obtained with the rilpivirine tabiet that is now being evaluated in Phase 3 clinical trials. In contrast, both emtricitabine and tenofovir AUC and Cmax levels from Formulations 1 and 2 were bioequivalent to the commercial formulations of EMTRIVA® (Emtracitabine) and VIREAD® (tenofovir DF), respectively. The significantly higher exposure levels of rilpivirine observed from Formulations 1 and 2 in the bioequivalence study may be due to the direct physicochemical interactions between rilpivirine HCl and either emtricitabine or tenofovir DF. These results suggest that the formulation and the manufacturing process required significant modifications to achieve the desired rilpivirine exposures.

RPV PK Parameter	Test	Reference	% GMR (90% CI)
Formulation 1
C\|T1M	166 (25%)	109(28%)	154(147,161)
AUChst	3685 (22%)	2742 (29%)	136(130,143)
AUC_mf	4005 (23%)	3021 (32%)	135 (129,142)
Formulation 2
c '-'mix	163 (24%)	109 (28%)	151 (144,158)
AUC^	3659 (24%)	2742 (29%)	135(129,141)
AUCmf	3983 (24%)	3021 (32%)	134(128,141)

C_mix: ng/mL, AUC: ng*hr/mL

The invention will now be illustrated by the following non-Iimiting Examples.

Examples

Exampie 1. Synthesis of a Représentative Bilayer Tablet of the Invention

In one embodiment of the invention the manufacturing procedure can be broken down into multiple segments: fluid-bed granulation and drying of rilpivirine HCl, high shear wet granulation of emtricitabine and tenofovir DF, milling and blending of each granulation, bilayer tableting, film-coating ofthe bulk tablets, and packaging. The stepwise procedure is detailed below. To accommodate the equipment capacities, the in-process product may be granulated and dried in multiple portions, which are then combined prior to the final milling and blending steps. As illustrated in Figure 4, a représentative tablet of the invention can be prepared as foilows.

Fluid-Bed Granulation of Rilpivirine HCl ) XVeigh rilpivirine HCl and the excipients (lactose monohydrate and croscarmellose sodium). Correct the weight of rilpivirine HCl based on the drug content factor, with a concomitant réduction in the weight of lactose monohydrate.

2) XVeigh purified water, polysorbate 20, and povidone. Mix in 2 steps in a stainless steel vessel to form the granulation binder fluid. First, add povidone, then add polysorbate 20 and mix until fully dissolved.

3) Add rilpivirine HCl, lactose monohydrate, and croscarmellose sodium to the fluid-bed granulator/dryer and fluidize the bed to pre-mix the components.

4) Spray the entire volume of binder solution while maintaining powder bed fluidization.

5) After solution addition, dry the granules in the fluid-bed granulator/dryer to a suitable moisture content as determined by loss on drying (LOD).

Milling and Blendinç ofRilnivirine Blend

6) Transfer the dried granulation through a mill for particle size réduction.

7) Add the dried, milled granules as well as extragranular lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium and blend in a biender.

8) Add extragranular magnésium stéarate and blend.

Wet Granidation of Emtricitabine/Tenofox'ir DF

9) Weigh emtricitabine, tenofovir DF, and excipients (pregelatinîzed starch, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, and magnésium stéarate). Correct the weight of tenofovir DF and emtricitabine based on the drug content factor and correspondingly adjust the weight of lactose monohydrate.

10) Add emtricitabine, tenofovir DF, and the intragranularexcipients (pregelatinîzed starch, croscarmellose sodium, microcrystalline cellulose, and lactose monohydrate) to the high shear granulator/mixer and blend with the impeller setto low speed.

11) Add water to the dry blend while mixing with the impeller (mixer) and granulator (chopper) to form the wet granulation. After water addition, wet mass to complété the granule formation.

12) Mill the wet granulated material.

Fluid-Bed Drying

13) Transfer the wet granulation to the fluid bed dryer and dry the granules to suitable moisture content as determined by loss on drying (LOD).

Milling and Blending of Enitricitabine/Tenofovir DF Blend

14) Transfer the dried granules and the extragranular excipient (croscarmellose sodium) through a mill for particle size réduction.

15) Blend the mixture.

16) Add magnésium stéarate to the mixture and blend.

Tableting

17) Compress the emtricitabine/tenofovir DF final powder blend followed by the rilpivirine final powder blend to target weight and hardness on a bilayer tablet press.

Film-Coatins

18) Film-coat the uncoated tablet cores with an aqueous suspension of Opadry II Purple

33G100000 to achieve the target weight gain.

Example 2. Synthesis of a Représentative Trilayer Tablet of the Invention

In one embodiment of the invention the manufacturing can be broken down into multiple segments: fluid-bed granulation and drying ofrilpivirine HCl, high shear wet granulation of emtricitabine and tenofovir DF, milling and blending of each granulation, trilayer tableting, filmcoating of the bulk tablets, and packaging. The stepwise procedure is detailed below. To accommodate the equipment capacities, the in-process product may be granulated and dried in multiple portions, which are then combined prior to the final milling and blending steps. As illustrated in Figure 5, a représentative tablet of the invention can be prepared as follows.

Fluid-Bed Granulation ofRilpivirine HCl

1) Weigh rilpivirine HCl and the excipients (lactose monohydrate and croscarmellose sodium). Correct the weight of rilpivirine HCl based on the drug content factor, with a concomitant réduction in the weight of lactose monohydrate.

2) Weigh purified water, polysorbate 20, and povidone. Mix in 2 steps in a stainless steel vessel to form the granulation binder fluid. First, add povidone, then add polysorbate 20 and mix until fuily dissolved.

4) Spray the entire quantity of binder solution while maintaining powder bed fluidization to ensure uniform granule growth.

5) After solution addition, dry the granules in the fluid-bed granulator/dryer to a suitabie moisture content as determined by loss on drying (LOD).

Milling and Blending qf Rilpivirine Blend

6) Transfer the dried granulation through a mill for particle size réduction.

7) Add the dried, milled granules as well as extragranular lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium and blend in a blender.

8) Add extragranular magnésium stéarate and blend.

Wet Granulation of EmtricitabinefTenofbvir DF

9) Weigh emtricitabine, tenofovir DF, and excipients (pregelatinized starch, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, and magnésium stéarate). Correct the weight of tenofovir DF and emtricitabine based on the drug content factor and correspondingly adjust the weight of lactose monohydrate.

10) Add emtricitabine, tenofovir DF, and the intragranular excipients (pregelatinized starch, croscarmellose sodium, microcrystalline cellulose, and lactose monohydrate) to the high shear granulator/mixer and blend with the impeller set to low speed.

) Add water to the dry blend while mixing with the impeller (mixer) and granulator (chopper) to form the wet granulation. After water addition, wet mass to complété the granule formation.

12) Mill the wet granulated material.

Fluid-Bed Drxing

Milling and Blending of Emtricitahine/Tenofovir DF Blend

14) Transfer the dried granules and the extragranular excipient (croscarmellose sodium) through a mill forparticle size réduction.

15) Blend the mixture.

16) Add magnésium stéarate to the mixture and blend.

Tableting

17) ' Compress the emtricitabine/tenofovir DF final powder blend followedby the rilpivirine final powder blend to target weight and hardness on a trilayer tablet press with lactose monohydrate or microcrystalline cellulose as the middle layer.

Film-Coating

33G100000 to achieve the target weight gain.

Example 3. Synthesis of a Représentative Bilayer Tablet of the Invention

To accommodate the equipment capacities, the in-process product may be granulated and dried in multiple portions, which are then combined prior to the final milling and blending steps.

As illustrated in Figure 6, a représentative tablet of the invention can be prepared as follows.

Wet Granulation ofEmtrîcitabine/Tenofovir DF

1) Weigh emtricitabine, tenofovir DF, and excipients (pregelatinized starch, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, and magnésium stéarate). Correct the weight of tenofovir DF and emtricitabine based on the drug content factor and correspondingly adjust the weight of lactose monohydrate.

«

2) Add emtricitabine, tenofovîr DF, and the intragranular excipients (pregelatinized starch, croscarmellose sodium, microcrystalline cellulose, and lactose monohydrate) to the high shear granulator/mixer and blend with the impeller set to low speed.

3) Add water to the dry blend while mixing with the impeller (mixer) and granulator (chopper) to form the wet granulation. After water addition, wet mass to complété the granule formation.

4) Mil! the wet granulated material.

Fluid-Bed Drying

5) Transfer the wet granulation to the fluid bed dryer and dry the granules to suitable moisture content as determined by loss on drying (LOD).

Milling and Blending of Emtricitabine/Tenofovir DF Blend

6) Transfer the dried granules and the extragranular excipient (croscarmellose sodium) through a mil] for particle size réduction.

7) Blend the mixture.

158) Add magnésium stéarate to the mixture and blend.

Table ting

9) Compress the emtricitabine/tenofovir DF final powder blend to target weight and hardness on a single layer tablet press

RPV Film-Coatinç

2010) Préparé a solution or suspension of R.PV in an organic solvent or aqueous media. The solution or suspension can contain additional excipients such as povidione, polyethylene glycol, hypromellose, lactose monohydrate, and/or a wetting agent to aid in the adhesion of the film-coat to the tablet surface.

11) Film-coat the uncoated tablet cores with the solution/suspension of polymer and rilpivirine

HCl to achieve the target weight gain for potency.

Example 4. Préparation of Représentative Tablets of the Invention

Bilayer formulations were investigated where one layer contaîned riîpivirine HCl (hereafter designated as the riîpivirine layer) and the other layer contaîned emtricitabine and tenofovir DF. This approach was employed to minimize any potential physicochemical interactions between riîpivirine HCl and emtricitabine and tenofovir DF. The bilayer formulation approach involved two separate granulation processes in which riîpivirine HCl was wet granulated using a fluîd-bed granulation process and emtricitabine and tenofovir DF were cogranulated using a high shear wet granulation process. The two granulations were physically separated by compressing the two blends into a bilayer tablet (Formulations 3 and 4). The quantitative compositions for Formulations 3 and 4 are listed in Table 4.1 and Table 4.2 respectively. While Formulations 3 and 4 utilized the same manufacturing process, the formulation composition of the riîpivirine HCl granulation in each of the formulations differed in the relative proportion of the excipients used.

t

Table 4.1. Quantitative Composition of Formulation 3 Tablets

Ingrédient	Unit Formula for FTC/RPV/TDF Tablets (mg/tablet)
RPV Layer
Rilpivirine HCl	27.5'
Microcrystalline Cellulose	60.0
Lactose Monohydrate	189.8
Povidone	3.3
Polysorbate 20	0.4
Croscarmellose Sodium	16.1
Magnésium Stéarate	3.0
Total Layer Weight	300.0

FTC/TDF Layer

Emtricitabîne	200.0
Tenofovir DF	300.0^k
Microcrystalline Cellulose	150.0
Lactose Monohydrate	80.0
Pregelatinized Stareh	50.0
Croscarmellose Sodium	60.0
Magnésium Stéarate	10.0
Total Layer Weight	850.0
Film Coat Components Opadry II Purple 33G100000	34.5
Total Tablet Weight	1184.5

Equivalent to 25.0 mg rilpivirine free base.

Equivalent to 245 mg of tenofovir disoproxil

Table 4.2. Quantitative Composition of Formulation 4 Tablets
Ingrédient	Unit Formula for FTC/RPV/TDF Tablets (mg/tablet)
RPV Layer’
Riîph irine HCl	27.5*
Microcrystalline Cellulose	45.0
Lactose Monohydrate	134.3
Povidone	3.3
Polysorbate 20	0.4
Croscarmellose Sodium	12.4
Magnésium Stéarate	23
Total Layer Weight	225.0
FTC/TDF Layer
Emtricitabine	200.0
Tenofovir DF	300.0^b
Microcrystalline Cellulose	150.0
Lactose Monohydrate	80.0
Pregelatinized Starch	50.0
Croscarmellose Sodium	60.0
Magnésium Stéarate	10.0
Total Layer Weight	850,0
Film Coat Components
Opadry II Purple 33G100000	32.3
Total Tablet Weight	11073
a Equivalent to 25.0 mg rilpivirine free base.
b Equivalent to 245 mg of tenofovir disoprosil

Formulations 3 and 4 were designed to mînimize the formulation and manufacturing process différences between the fixed-dose combination tablets and the formulation currently in clinical trials by using the existing intragranular RPV formulation and iluid-bed granulation process. In addition, the rilpivirine HCl was separated from emtricitabine and tenofovir DF. This was

I accomplîshed through a bilayer compression process to produce the tablets. The emtricitabine/tenofovir DF powder blend was produced by the same manufacturing process and using the same intragranular composition for TRUVADA ® (emtricitibine 200 mg ! tenofovir DF 300 mg). The weight disparity between rilpivirine and emtricitabine/tenofovir DF layers required dilution of the rilpivirine HCi granulation to ensure a robust tablet manufacturing process. The layer weights in Formulations 3 and 4 were accommodated by adjusting the concentrations ofthe excipients in the rilpivirine layer with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnésium stéarate.

Example 5. Bioavailability of Formulations 3 and 4

This study evaluated the bioequivalence of Formulation 3 from Example 4 to coadministration of the three individual dosage forms (FTC+RPV+TDF, Reference)

A randomized, single-dose, open-label, Phase 1 study in healthy adults under fed conditions. Serial blood samples were obtained over 192 hours following oral administration of each treatment and PK parameters calculated. Formulation bioequivalence was assessed by 90% confidence intervals (CI) for the ratio of géométrie least square means (GMR) for C_mix, AUCbst and AUCjnf for each drug of the Test versus Reference treatment.

Results: 36 subjects enrolled and 34 completed the study. Ail treatments were generally well tolerated; most adverse events seen were mild in severity. The arithmetic mean and the géométrie mean ratio (GMR), along with the 90% confidence interval, of the PK parameters are presented below.

PK Parameter	Formulation 3	Reference	% GMR (90% Confidence Interval)
RPV
Cnut	110	95	116(108,124)
AUC_bsl	2855	2467	116(109,123)
AUCinf	3167	2739	116(109,124)
FTC
r	1714	1625	105(100, lll)
AUC^,	9361	9366	100(98,102)
AUCmf	9581	9595	100(98,102)

t

TFV
	315	284	lll (104, H8)
AUCust	3053	29S9	102 (99,105)
AUC_mf	3264	3200	102 (99,105)

Cmav ng/mL, AUC: ng*hr/mL

PK Parameter	Formulation 4	Reference	% GMR (90% Confidence Interval)
RPV
Cmi,	115	95	122(114,130)
AUC_bil	2889	2467	117(110,124)
AUC^f	3211	2739	117(110,125)
FTC
c™,	1754	1625	108(103, 113)
AUCbrt	9433	9366	101 (99,102)
AUC,_nf	9646	9595	101 (98,103)
TFV
C™,	323	284	114(107,121)
AUCfast	3110	2989	104(101,107)
AUC^	3333	3200	104(101,107)

C_max: ng/mL, AUC: ng*hr/mL

Formulation 3 was found to produce human plasma concentrations of each of the three agents that were équivalent to the plasma concentrations produced by the administration of the 5 individual agents. Formulation 4 from Example 4 did not produce human plasma concentrations of each of the three agents that were équivalent to the plasma concentrations produced by the administration of the individual agents.

Formulation 3 and Formulation 4 difier in the weight of extragranular excipients and in the amount of croscarmellose sodium présent. The bioequivalent formulation (Formulation 3) 10 has significantly higher (38%) amounts of extragranular excipients (microcrystalline cellulose and lactose monohydrate) and croscarmellose sodium in the rilpivirine layer than Formulation 4. Laboratory data showed that the intrinsic dissolution rate of rilpivirine was increased in the presence of emtricitabine and/or tenofovir DF suggesting an increased solubility could contribute to a higher rilpivirine bioavailability when co-formulated with emtricitabine and tenofovir DF. It »

may be postulated that the higher amounts of diluents in the rilpivirine layer of Formulation 3 that was bioequivalent to the rilpivirine single agent reference tablet could hâve served to lessen the extent of contact and interactions between rilpivirine and emtricitabine and/or tenofovir DF and achieve bioequivalence.

In addition, the higher amount of croscarmellose sodium, a superdisintegrant, leads to faster layer disintegration and séparation of the rilpivirine layer from the emtricitabine/tenofovir DF layer minimizing any potential interactions between rilpivirine with emtricitabine and/or tenofovir DF. The concentration of croscarmellose sodium, a basifying excipient, in the rilpivirine layer also had an unexpected effect on the rilpivirine dissolution rate, Higher concentrations of this superdisintegrant, unexpectedly decreased the dissolution rate as shown in Figure 9. This is possibly due to the basifying nature of this excipient.

Example 6. Stability of Components of Formulation 3

Identity and strengths of the APIs and dégradation products were determined using an HPLC method, which employed a 4.6 x 250-mm C-12 column (4-pm particle size) for chromatographie séparation by reversed-phase chromatography using a mobile phase consisting of ammon2ium acetate buffer and acetonitrile with gradient elution over approximately 60 minutes. Composite samples of 10 tablets were dissolved and diluted to final concentrations of approximately 0.08 mg/mL RPV, 0.64 mg/mL FTC, and 0.96 mg/mL TDF with a 4:3:3 pH 3 phosphate buffer:acetonitrile:methanol solution. The strength and dégradation product content of FTC, RPV, and TDF were determined by HPLC using area normalization and extemal reference standards at a wavelength of 262 nm. The stability data for 30 count tablets stored at 40°C/75% RH in induction sealed bottles containing 3 g silica gel desiccant are summarized in the table below and demonstrate acceptable chemical stability under accelerated storage conditions.

		Lot Number
Time Point	1	2	3
Rilpivirine Strength	(%) / Total Dégradation Con	lent (%)
0 month	100.2/0.0	100.8/0.0	99.5/0.0
1 month	100.4/0.0	100.8/0.0	99.6/0.0
3 months	100.3/0.0	99.5/0.0	99.2/0.0

Emtricitabine Strength (%)/ Total Dégradation Content (%)

0 month	99.1/0.0	99.1/0.0	102.6/0.0
1 month	99.5/0.0	100.2/0.0	102.6/0.0
3 months	98.5/0.0	97.1/0.1	100.5/0.1
Tenofovir Disoproxil Fumarate Strength (%) / Total Dégradation Content (%)
0 month	101.0/0.6	102.1/0.7	102.0/0.8
1 month	101.1/0.7	102.7/0.9	101.5/1.0
3 months	100.5/0.9	99.9/1.2	99.7/13

Example 7. Stability of Components of Formulation 4

The stability data for 30 count tablets stored at 40°C/75% RH in induction sealed bottles containing 3 g silica gel desiccant are summarized in the table below and demonstrate acceptable chemical stability under accelerated storage conditions comparable to Formulation 3.

Time Point	1	Lot Number 2	3
Rilpivirine Streng	;th (%) / Total Dégradation Content (·/·)
0 month	100.3/0.2	99.4/0.1	100.7/0.1
1 month	100.9/0.2	99.1/0.1	97.6/0.1

Emtricitabine Strength (%) / Total Dégradation Content (%)

0 month	98.0/0.0	103.1/0.0	100.3/0.0
1 month	99.6/0.0	104.4/0.0	100.8/0.0
Tenofovir Disoproxil Fumarate Strength (¾) / Total Dégradation Content (·/·)
0 month	101.7/0.6	99.4/0.7	102.6/0.8
1 month	103.2/0.7	100.2/0.9	102.7/0.9

t

Example 8. Food Effect

Formulation 3 was evaluated in a comparative bîoavailability study to assess the effect of food on the exposure of rilpivirine HCl when dosed in the reference group as three individual tablets containing emtricitabine, rilpivirine HCl, and tenofovir DF.

The “fed” state or “fed conditions” refers to administering the study drugs within 5 minutes of completing a standardized meal (breakfast). Subjects were restricted from food consumption for approximately 4 hours after dosing. A meal (standardized lunch) was provided to subjects after the 4-hour postdose blood draw. Ail meals and/or snacks were standardized for ail subjects and were to be similar in calorie and fat content and taken at approximately the same time each day.

• 10 The standardized breakfast on dosing days contained approximately 400 calories (kcal) and approximately 13 g of fat.

The “fasted” state refers to administering the study drugs in the absence of food. Subjects were fasted ovemight, administered the study drugs, and then restricted from food consumption for approximately 4 hours after dosing. A meal (standardized lunch) was provided to subjects after 15 the 4-hour postdose blood draw.

A comparison of the mean values of the pharmacokinetic parameters are presented below along with the mean values of the Reference group under fed conditions. The AUC values for Formulation 3 under the fasted state are identical to the Reference group under fed conditions. The Reference group under the fasted state shows a 26% réduction in the AUC values as compared to the fed conditions.

PK Parameter	Reference Fed (n=34)	Formulation 3 Fasted (n=15)	Reference Fasted (n=15)
RPV
C™,	95	77	63
AUChrt	2467	2510	1960
AUCinf	2739	2730	2170

C_max: ng/mL, AUC: ng*hr/mL

Ali publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various spécifie and preferred embodiments and techniques. However, it should be

V · t understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

What is claimed is:

1. A tabiet comprising a first layer and a second layer wherein; a) the first layer comprises rilpivirine HCl and is substantially free of tenofovir disoproxil fumarate; b) the second layer comprises tenofovir disoproxil fumarate and is substantially free of rilpivirine HCl; and c) the tabiet further comprises emtricitabine.
2. The tabiet of claim 1 wherein the first layer does not comprise emtricitabine.
3. The tabiet of claim 1 wherein the second layer comprises emtricitabine.
4. The tabiet of any one of claims 1-3 which comprises 27.5 ± 1.4 mg of rilpivirine HCl.
5. The tabiet of any one of claims 1-4 which comprises 200 ± 10.0 mg of emtricitabine.
6. The tabiet of any one of claims 1 -5 which comprises 300 ± 15.0 mg of tenofovir disoproxil fumarate.
7. The tabiet of any one of claims 1 -6 wherein the first layer further comprises one or more diluents, disintegrants, binders, or lubricants.
8. The tabiet of claim 7 wherein the total weight of the first layer is 275 ± 75 mg.
9. The tabiet ofclaim 7 wherein the total weight ofthe first layer is greater than 225 mg.
10. The tabiet of claim 8 wherein the total weight of the first layer is 275 ± 50 mg.
11. The tabiet of any one of claims 1-10 wherein the first layer comprises a basifying agent.
12. The tabiet of claim 11 wherein the basifying agent is selected from croscarmellose sodium, calcium carbonate, sodium hydroxide, aluminum oxide, alkali métal hydroxides, alkaline earth métal hydroxides, aluminum hydroxide, dihydroaluminum, sodium carbonate, ammonium hydroxides, magnésium carbonate, magnésium stéarate, piperazine, sodium acetate, sodium citrate, sodium tartrate, sodium maleate, and sodium succinate and mixtures thereof.
13. The tablet of any one of claims 1-12 wherein the first layer comprises croscarmellose

5 sodium, and polysorbate 20.
14. The tablet of any one of claims 1-12 wherein the first layer comprises lactose monohydrate, povidone, croscarmellose sodium, polysorbate 20, microcrystalline cellulose, and magnésium stéarate.
15. The tablet of any one of claims 1-14 wherein the second layer comprises microcrystalline cellulose and croscarmellose sodium.
16. The tablet of any one of claims 1-14 wherein the second layer comprises lactose

15 monohydrate, pre-gelatinized starch, microciystalline cellulose, croscarmellose sodium, and magnésium stéarate.
17. The tablet of any one of claims 1-16 wherein the first layer is in contact with the second layer.
18. The tablet of any one of claims 1-16 that further comprises a third layer that is between . and that séparâtes the first layer and the second layer.
19. The tablet of claim 18 wherein the third layer comprises lactose monohydrate and/or

25 microcrystalline cellulose.
20. The tablet of any one of claims 1-6 wherein the first layer is a polymeric film coating that is in contact with the second layer.

30
21. The tablet of claim 20 wherein the first layer is a polymeric film coating that completely covers the second layer.
22. The tablet of claim 3 wherein the first layer comprises:

Ingrédient

Rilpivirine HCl

Microcrystalline Cellulose

Polysorbate 20

Croscarmellose Sodium

Unit Formula for Tablets (mg/tablet)

27.5 ±1.4

60.0 ± 3

0.4 ± 0.02

16.1 ±0.8 and the second layer comprises:

Ingrédient Unît Formula for Tablets (mg/tablet) Emtricitabine 200 ±10 Tenofovir disoproxil fumarate 300 ± 15 Microcrystalline Cellulose 150 ±7.5 Croscarmellose Sodium 60±3.
23. The tablet of claim 3 wherein the first layer consists of:

Ingrédient Unit Formula for Tablets (mg/tablet) Rilpivirine HCl 27.5 Microcrystalline Cellulose 60.0 Lactose Monohydrate 189.8 Povidone 3.3 Polysorbate 20 0.4 Croscarmellose Sodium 16.1 Magnésium Stéarate 3.0

and the second layer consists of:

Unit Formula for Tablets (mg/tablet)

Ingrédient

Emtricitabine 200.0 Tenofovir disoproxil fumarate 300.0 Microcrystalline Cellulose 150.0 Lactose Monohydrate 80.0 Pregelatinized Starch 50.0 Croscarmellose Sodium 60.0 Magnésium Stéarate 10.0.
24. The tablet of claim 18 wherein the first layer consists of:

Ingrédient Unît Formula for Tablets (mg/tablet) Rilpivirine HCl 27.5 Microcrystalline Cellulose 60.0 Lactose Monohydrate 189.8 Povidone 3.3 Polysorbate 20 0.4 Croscarmellose Sodium 16.1 Magnésium Stéarate 3.0

the second layer consists of:

Ingrédient

Emtricitabine

Tenofovir disoproxil fumarate Microciystalline Cellulose Lactose Monohydrate Pregelatinized Starch Croscarmellose Sodium Magnésium Stéarate

Unit Formula for Tablets (mg/tablet)

200.0

300.0

150.0

800

50.0

60.0

10.0 and the third layer comprises 150 ± 8.0 mg of microcrystalline cellulose or lactose monohydrate, or a mixture thereof.
25. The tablet of any one of claims 1-19 and 22-24 that further comprises a film coating.
26. The tablet of claim 25 wherein the film coating comprises 34 ± 12 mg of Opadry Π Purple

5 33G100000.

27. A tablet having a first layer that consists of;

Ingrédient mg Rilpivirine HCl 27.5 Microcrystalline Cellulose 60.0 Lactose Monohydrate 189.8 Povidone . · 33 Polysorbate 20 0.4 Croscarmellose Sodium 16.1 Magnésium Stéarate 3.0 Total Layer Weight 300.0

10 a second layer that consists of:

Ingrédient mg Emtricitabine 200.0 Tenofovir DF 300.0¹¹ Microcrystalline Cellulose 150.0 Lactose Monohydrate 80.0 Pregelatinized Starch 50.0 Croscarmellose Sodium 60.0 Magnésium Stéarate 10.0 Total Layer Weight 850.0

and a coating that consists of:

I

Ingrédient mg Opadry II Purple 33G100000 34.5 Total Tablet Weight 1184.5.

28. The tablet ofany one of claims l-l9 wherein at least about 5.4 weight percent of the first layer is croscarmellose sodium and at least about 63.3 weight percent of the first layer is lactose monohydrate.
29. The tablet of any one of claims l -21 wherein less than about 12.2 weight percent of the first layer is rilpivirine hydrochloride.
30. The tablet of any one of claims l-21 wherein less than about 12 weight percent of the first layer is rilpivirine hydrochloride.
31. The tablet of claim 1 wherein the first layer comprises 27.5 ± 1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 230 mg.
32. A tablet prepared as described herein.
33. Use of rilpivirine HCl, tenofovir disoproxil fumarate and emtricitabine in the manufacture of a tablet having a first layer and a second layer, for treating HIV infection in a human by administration of the tablet to the human, wherein the first layer comprises rilpivirine HCl and is substantially free of tenofovir disoproxil fumarate and the second layer comprises tenofovir disoproxil fumarate and is substantially free of rilpivirine HCI.
34. The use of claim 33, wherein administration of the tablet to the human when fed achieves rilpivirine AUC that is no more than 25% greater than rilpivirine AUC aehieved following administration of the tablet to the human when fasted.
35. The use of claim 33, wherein administration of the tablet to the human when fed achieves rilpivirine C_max that is no more than 25% greater than rilpivirine C_mM aehieved following administration of the tablet to the human when fasted.
36. A tablet as described in any one of daims l-32 for use in a method of prophylactic or therapeutic treatment of an HIV infection, wherein riîpivirine AUC achieved following

5 administration to the human when fed is no more than about 25% greater than riîpivirine AUC achieved when administered to the human when fasted.
37. A tablet as described in any one of daims l-32 for use in a method of prophylactic or therapeutic treatment of an HIV infection, wherein riîpivirine C_max achieved following

10 administration to the human when fed is no more than about 25% greater than riîpivirine C_matachieved when administered to the human when fasted.
38. A tablet as described in any one of daims 1-32 for use in a method of prophylactic or therapeutic treatment of an HIV infection.
39. The use of a tablet as described in any one of daims 1-32 for preparing a médicament for treating HIV infection in a human.