U.S. patent application number 16/987081 was filed with the patent office on 2021-02-25 for therapeutic compositions for treatment of human immunodeficiency virus.
The applicant listed for this patent is Gilead Sciences, Inc.. Invention is credited to Benjamin Micah Collman, Lei Hong, Joanna M. Koziara.
Application Number | 20210052502 16/987081 |
Document ID | / |
Family ID | 1000005197404 |
Filed Date | 2021-02-25 |
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United States Patent
Application |
20210052502 |
Kind Code |
A1 |
Collman; Benjamin Micah ; et
al. |
February 25, 2021 |
THERAPEUTIC COMPOSITIONS FOR TREATMENT OF HUMAN IMMUNODEFICIENCY
VIRUS
Abstract
A solid oral dosage form is provided, comprising a compound of
Formula I or a pharmaceutically acceptable salt thereof, tenofovir
alafenamide or a pharmaceutically acceptable salt thereof, and
emtricitabine or a pharmaceutically acceptable salt thereof.
Inventors: |
Collman; Benjamin Micah;
(San Mateo, CA) ; Hong; Lei; (Cupertino, CA)
; Koziara; Joanna M.; (Foster City, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gilead Sciences, Inc. |
Foster City |
CA |
US |
|
|
Family ID: |
1000005197404 |
Appl. No.: |
16/987081 |
Filed: |
August 6, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16713380 |
Dec 13, 2019 |
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16987081 |
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15346335 |
Nov 8, 2016 |
10548846 |
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16713380 |
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62399999 |
Sep 26, 2016 |
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62253042 |
Nov 9, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 31/18 20180101;
A61K 31/513 20130101; A61K 9/209 20130101; A61K 9/0053 20130101;
A61K 31/553 20130101; A61K 9/2095 20130101; A61K 9/2086 20130101;
A61K 31/5365 20130101; A61K 9/2013 20130101; A61K 9/28 20130101;
A61K 9/2054 20130101; A61K 31/675 20130101 |
International
Class: |
A61K 9/24 20060101
A61K009/24; A61K 9/20 20060101 A61K009/20; A61K 31/513 20060101
A61K031/513; A61K 31/675 20060101 A61K031/675; A61K 31/553 20060101
A61K031/553; A61P 31/18 20060101 A61P031/18; A61K 9/00 20060101
A61K009/00; A61K 9/28 20060101 A61K009/28; A61K 31/5365 20060101
A61K031/5365 |
Claims
1-30. (canceled)
31. A method of producing a multilayer tablet comprising the
compound of Formula I: ##STR00011## or a pharmaceutically
acceptable salt thereof, tenofovir alafenamide or a
pharmaceutically acceptable salt thereof, and emtricitabine or a
pharmaceutically acceptable salt thereof, wherein the method
comprises (a) compressing the a compound of Formula I or a
pharmaceutically acceptable salt thereof as a first layer, and (b)
compressing the tenofovir alafenamide or a pharmaceutically
acceptable salt thereof and emtricitabine or a pharmaceutically
acceptable salt thereof as a second layer.
32. The method of claim 31, wherein the first layer and second
layer are compressed separately and subsequently combined.
33. The method of claim 31, wherein the first layer is formed by
compression and subsequently the second layer is compressed onto
the first layer.
34. The first layer obtainable by the method of claim 31.
35. The second layer obtainable by the method of claim 31.
36-51. (canceled)
52. The method of claim 31, wherein the tablet comprises 50 mg of
the compound of Formula I or a pharmaceutically acceptable salt
thereof, 25 mg tenofovir alafenamide or a pharmaceutically
acceptable salt thereof, and 200 mg emtricitabine or a
pharmaceutically acceptable salt thereof wherein the tablet has a
total weight of less than about 1000 mg.
53. The method of claim 31, wherein the tablet comprises 50 mg of
the compound of Formula I as a pharmaceutically acceptable salt
thereof, 25 mg tenofovir alafenamide as a pharmaceutically
acceptable salt thereof, and 200 mg emtricitabine.
54. The method of claim 53, wherein the tablet comprises 52 mg of
the sodium salt of the compound of Formula I and 28 mg tenofovir
alafenamide hemifumarate.
55. The method of claim 54, wherein the tablet the tablet has a
total weight of less than about 800 mg.
56. The method of claim 54, wherein the tablet has a total weight
of less than about 730 mg.
Description
CROSS-REFERENCE TO THE RELATED APPLICATIONS
[0001] This patent application claims the benefit of priority of
U.S. Application Ser. No. 62/253,042, filed Nov. 9, 2015 and of
U.S. application Ser. No. 62/399,999, filed Sep. 26, 2016. The
content of each of these provisional applications is hereby
incorporated herein in its entirety.
TECHNICAL FIELD
[0002] Pharmaceutical formulations suitable for treating viral
infections such as HIV are provided, in particular solid oral
dosage forms including the compound of Formula I, emtricitabine and
tenofovir alafenamide.
BACKGROUND
[0003] Human immunodeficiency virus, type 1 (HIV-1) infection is a
life-threatening and serious disease of major public health
significance, with approximately 35 million people infected
worldwide (Joint United Nations Programme on HIV/AIDS (UNAIDS).
Global report: UNAIDS report on the global AIDS epidemic, 2013).
Standard of care for the treatment of HIV-1 infection uses
combination antiretroviral therapy (ART) to suppress viral
replication to below detectable limits, increase CD4 cell counts,
and halt disease progression.
[0004] There is also a need for medications to serve populations
with limited treatment options (e.g., children, women, and the
elderly). In certain situations, these populations may have
difficulty maintaining treatment because of pill burden (number of
pills to take each day, as well as different combinations of pills)
or the size of the pills themselves, once they are coformulated
into a multidrug composition. For example, there is currently no
fixed dose combination registered for once a day dosing (i.e., QD)
for very young children (e.g., younger than age 12 years).
[0005] A goal of antiretroviral therapy is to achieve viral
suppression in the HIV infected patient. Treatment guidelines
published by the United States Department of Health and Human
Services provide that achievement of viral suppression requires the
use of combination therapies, i.e., several drugs from at least two
or more drug classes. In addition, decisions regarding the
treatment of HIV infected patients are complicated when the patient
requires treatment for other medical conditions (e.g., metformin,
rifampin, HCV antivirals, hormonal contraceptives, etc.). Because
the standard of care requires the use of multiple different drugs
to suppress HIV, as well as to treat other conditions the patient
may be experiencing, the potential for drug-drug interaction is a
criterion for selection of a drug regimen. As such, there is a need
for antiretroviral therapies having a decreased potential for
drug-drug interactions (e.g., those that affect transporters (e.g.,
OCT-2) or activate receptors (e.g., PXR).
SUMMARY
[0006] All the compositions and oral dosage forms herein include a
compound of Formula I,
(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13-
,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-1-
0-carboxamide, having the following structure:
##STR00001##
or a pharmaceutically acceptable salt thereof.
[0007] In certain embodiments, the pharmaceutically acceptable salt
of the compound of Formula I is a compound of Formula II, sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,-
13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin--
8-olate, having the following structure:
##STR00002##
[0008] The inventors have successfully formulated an oral dosage
form containing the compound of Formula I, tenofovir alafenamide
and emtricitabine. This oral dosage form is suitable for use in
medicine, and in particular in treating viral infections such as
HIV.
[0009] In one aspect, a solid oral dosage form comprising the
compound of Formula I or a pharmaceutically acceptable salt
thereof, tenofovir alafenamide or a pharmaceutically acceptable
salt thereof, and emtricitabine or a pharmaceutically acceptable
salt thereof is provided. In certain embodiments, the dosage form
comprises 50 mg of the compound of Formula I or a pharmaceutically
acceptable salt thereof, 25 mg tenofovir alafenamide or a
pharmaceutically acceptable salt thereof, and 200 mg emtricitabine.
For instance, in certain embodiments, the dosage form comprises 50
mg of the compound of Formula I as a pharmaceutically acceptable
salt thereof, 25 mg tenofovir alafenamide as a pharmaceutically
acceptable salt thereof, and 200 mg emtricitabine. In certain
embodiments, the dosage form comprises 52 mg of the compound of
Formula II, 28 mg tenofovir alafenamide hemifumarate, and 200 mg
emtricitabine.
[0010] In another aspect, a solid oral dosage form comprising 75 mg
of the compound of Formula I as a pharmaceutically acceptable salt
thereof, 25 mg tenofovir alafenamide as a pharmaceutically
acceptable salt thereof, and 200 mg emtricitabine is provided. In
certain embodiments, a solid oral dosage form comprising 75 mg of
the compound of Formula I or a pharmaceutically acceptable salt
thereof, 25 mg tenofovir alafenamide or a pharmaceutically
acceptable salt thereof, and 200 mg emtricitabine is provided. In
certain embodiments, a solid oral dosage form comprising 78 mg of
the compound of Formula II, 28 mg tenofovir alafenamide
hemifumarate, and 200 mg emtricitabine is provided.
[0011] The inventors have found that it is possible to formulate
solid oral dosage forms that are pharmaceutically acceptable (i.e.
pharmacologically efficacious and physically acceptable) while
reducing the total amount of excipients necessary to achieve an
acceptable pharmacokinetic profile. Accordingly, in one aspect a
solid oral dosage form is provided, comprising 50 mg of the
compound of Formula I or a pharmaceutically acceptable salt
thereof, 25 mg tenofovir alafenamide or a pharmaceutically
acceptable salt thereof, and 200 mg emtricitabine or a
pharmaceutically acceptable salt thereof, wherein the dosage form
has a total weight of less than 850 mg (e.g. less than 800 mg or
less than 730 mg or less than 700 mg).
[0012] In another one aspect a solid oral dosage form is provided,
comprising 75 mg of the compound of Formula I or a pharmaceutically
acceptable salt thereof, 25 mg tenofovir alafenamide or a
pharmaceutically acceptable salt thereof, and 200 mg emtricitabine
or a pharmaceutically acceptable salt thereof, wherein the dosage
form has a total weight of less than 850 mg (e.g. less than 800 mg
or less than 700 mg).
[0013] In another aspect, a coated tablet comprising 50 mg of the
compound of Formula I or a pharmaceutically acceptable salt
thereof, 25 mg tenofovir alafenamide or a pharmaceutically
acceptable salt thereof, and 200 mg emtricitabine or a
pharmaceutically acceptable salt thereof is provided.
[0014] In another aspect, a coated tablet comprising 75 mg of the
compound of Formula I or a pharmaceutically acceptable salt
thereof, 25 mg tenofovir alafenamide or a pharmaceutically
acceptable salt thereof, and 200 mg emtricitabine or a
pharmaceutically acceptable salt thereof is provided.
[0015] In another aspect, a tablet comprising 52 mg of the compound
of Formula II, 28 mg tenofovir alafenamide hemifumarate, and 200 mg
emtricitabine is provided.
[0016] In another aspect, a tablet comprising 78 mg of the compound
of Formula II, 28 mg tenofovir alafenamide hemifumarate, and 200 mg
emtricitabine is provided.
[0017] In another aspect, a tablet comprising (a) 50 mg of the
compound of Formula I or a pharmaceutically acceptable salt
thereof, (b) 25 mg tenofovir alafenamide or a pharmaceutically
acceptable salt thereof, and (c) 200 mg emtricitabine or a
pharmaceutically acceptable salt thereof is provided, wherein (a)
and (b) are segregated, and wherein the tablet has a total weight
of less than about 1.5 g (e.g., less than about 1 g). Typically,
(a) and (b) are present within separate layers in a multilayer
tablet.
[0018] In another aspect, a tablet comprising (a) 75 mg of the
compound of Formula I or a pharmaceutically acceptable salt
thereof, (b) 25 mg tenofovir alafenamide or a pharmaceutically
acceptable salt thereof, and (c) 200 mg emtricitabine or a
pharmaceutically acceptable salt thereof is provided, wherein (a)
and (b) are segregated, and wherein the tablet has a total weight
of less than about 1.5 g (e.g., less than about 1 g). Typically,
(a) and (b) are present within separate layers in a multilayer
tablet.
[0019] In another aspect, a tablet comprising from 6.5-11.0% w/w of
the compound of Formula I or a pharmaceutically acceptable salt
thereof, 3.0-4.5% w/w tenofovir alafenamide or a pharmaceutically
acceptable salt thereof, and 25-30% w/w emtricitabine or a
pharmaceutically acceptable salt thereof is provided, where the
weight percentages denote a proportion of the whole tablet. In some
embodiments, (a) the compound of Formula I is present as of the
compound of Formula II and/or (b) the tenofovir alafenamide is
present as tenofovir alafenamide hemifumarate.
[0020] In another aspect, a tablet comprising from 9.5-11.5% w/w of
the compound of Formula I or a pharmaceutically acceptable salt
thereof, 2.5-4.5% w/w tenofovir alafenamide or a pharmaceutically
acceptable salt thereof, and 26-33% w/w emtricitabine or a
pharmaceutically acceptable salt thereof is provided, where the
weight percentages denote a proportion of the whole tablet. In some
embodiments, (a) the compound of Formula I is present as of the
compound of Formula II and/or (b) the tenofovir alafenamide is
present as tenofovir alafenamide hemifumarate.
[0021] The inventors have found that the use of a fixed dose
combination may assist in achieving appropriate pharmacokinetic
parameters and/or adequate tablet stability. In addition, the use
of a multilayer tablet as a particular type of fixed dose
combination may also provide pharmacokinetic and/or stability
benefits. Accordingly, in another aspect a fixed dose combination
tablet comprising (a) the compound of Formula I or a
pharmaceutically acceptable salt thereof, (b) tenofovir alafenamide
or a pharmaceutically acceptable salt thereof, and (c)
emtricitabine or a pharmaceutically acceptable salt thereof is
provided. Additionally, multilayer tablet comprising (a) the
compound of Formula I or a pharmaceutically acceptable salt
thereof, (b) tenofovir alafenamide or a pharmaceutically acceptable
salt thereof, and (c) emtricitabine or a pharmaceutically
acceptable salt thereof is provided.
[0022] In another aspect, a kit comprising (a) a tablet comprising
the compound of Formula I or a pharmaceutically acceptable salt
thereof, tenofovir alafenamide or a pharmaceutically acceptable
salt thereof, and emtricitabine or a pharmaceutically acceptable
salt thereof, and (b) a desiccant (e.g. silica gel) is
provided.
[0023] Methods of producing solid oral dosage forms such as tablets
are also provided, as discussed in more detail below.
[0024] In addition, methods for treating patients are provided,
which are also discussed in more detail below.
BRIEF DESCRIPTION OF DRAWINGS
[0025] FIG. 1 shows the results of studies carried out on
Formulations F1, F2, and F3 to assess the dissolution of 78 mg of
the Compound of Formula II as a single agent compared to a bi-layer
using fasted simulated intestinal fluid as a dissolution
medium.
[0026] FIG. 2 shows the results of studies carried out on
Formulations F1 and F2 to assess the dissolution of 78 mg of the
Compound of Formula II as a single agent compared to a bi-layer
using fed simulated intestinal fluid as a dissolution medium.
[0027] FIG. 3 shows the results of studies carried out on
Formulations F1, F2, F4, F5, and F6 to assess the dissolution of 78
mg of the Compound of Formula II in tablets containing various
excipients.
[0028] FIG. 4 shows the results of studies carried out on
Formulations F7 and F8 to assess the dissolution of 52 mg of the
Compound of Formula II as a single agent compared to a bi-layer
using fasted simulated intestinal fluid as a dissolution
medium.
[0029] FIG. 5 is a flow diagram illustrating the preparation of a
tablet formulation containing the compound of Formula II.
[0030] FIG. 6 is a flow diagram illustrating the preparation of a
tablet formulation containing the compound of Formula II,
emtricitabine, and tenofovir alafenamide hemifumarate.
DETAILED DESCRIPTION
[0031] Typically, the oral dosage forms disclosed herein comprise
three active pharmaceutical ingredients: the compound of Formula I
(or a pharmaceutically acceptable salt thereof), tenofovir
alafenamide (or a pharmaceutically acceptable salt thereof), and
emtricitabine (or a pharmaceutically acceptable salt thereof).
(2R,5S,13aR)-8-Hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,-
13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-
-carboxamide
[0032]
(2R,5S,13aR)-8-Hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,-
7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaze-
pine-10-carboxamide (Formula I), is a potent HIV integrase
inhibitor with in vitro activity against wild type HIV-1. It has
the following formula (see WO2014/100323):
##STR00003##
[0033] Its IUPAC name is
(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13-
,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-1-
0-carboxamide. Its CAS name is
2,5-Methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,
2,3,4,5,7,9,13,13a-octahydro-8-hydroxy-7,9-dioxo-N-[(2,4,6-trifluoropheny-
l)methyl]-, (2R,5S,13aR). The compound of Formula I is a weak acid
with pKa of 8.6. The aqueous solubility of the compound of Formula
I free acid is pH-dependent, with solubility increasing with
increasing pH, with a maximum at pH 10.5. The chemical stability of
the compound of Formula I is also pH dependent, with maximum
stability at pH 4. The compound of Formula I is considered a BCS
Class 2 compound, with low solubility and high permeability.
[0034] Solid oral dosage forms disclosed herein include the
compound of Formula I, usually in the form of a pharmaceutically
acceptable salt. The compound of Formula I can be present within an
oral dosage form in solvated or unsolvated form, and references to
"Formula I" include both of these forms. Typically, the compound of
Formula I is in the form of the compound of Formula II, having the
formula below:
##STR00004##
[0035] In certain specific embodiments, solid oral dosage forms
containing 50 mg of the compound of Formula I, e.g. as about 52 mg
of the compound of Formula II, are provided.
[0036] In certain specific embodiments, solid oral dosage forms
containing 75 mg of the compound of Formula I, e.g. as about 78 mg
of the compound of Formula II, are provided.
[0037] As used herein, and in the absence of a specific reference
to a particular pharmaceutically acceptable salt and/or solvate of
the compound of Formula I (e.g. Formula II), any dosages, whether
expressed in e.g. milligrams or as a % by weight, should be taken
as referring to the amount of the compound of Formula I free acid,
i.e. the amount of:
##STR00005##
[0038] For example, therefore, a reference to "50 mg of the
compound of Formula I or a pharmaceutically acceptable salt and/or
solvate thereof" means an amount of the compound of Formula I or a
pharmaceutically acceptable salt and/or solvate thereof which
provides the same amount of the compound of Formula I as 50 mg of
the compound of Formula I free acid.
[0039] For example, therefore, a reference to "75 mg of the
compound of Formula I or a pharmaceutically acceptable salt and/or
solvate thereof" means an amount of the compound of Formula I or a
pharmaceutically acceptable salt and/or solvate thereof which
provides the same amount of the compound of Formula I as 75 mg of
the compound of Formula I free acid.
Tenofovir Alafenamide
[0040] Tenofovir alafenamide (TAF) is a nucleotide reverse
transcriptase inhibitor having the formula below (see WO02/08241
A2):
##STR00006##
[0041] Its IUPAC name is
(S)-isopropyl-2-(((S)--((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)me-
thyl)(phenoxy)phosphoryl)amino)propanoate. It is also referred to
as
{9-[(R)-2-[[(S)--[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphiny-
l]-methoxy]propyl]adenine}. Tenofovir alafenamide is a weak base,
with a pKa of 3.9. Its solubility increases with decreasing pH,
with a maximum solubility at about pH 3. Tenofovir alafenamide is
considered a BCS Class 3 compound, with high equilibrium solubility
and lower apparent permeability.
[0042] Solid oral dosage forms disclosed herein include tenofovir
alafenamide, usually in the form of a pharmaceutically acceptable
salt. Tenofovir alafenamide can be present within an oral dosage
form in solvated or unsolvated form, and references to "tenofovir
alafenamide" include both of these forms. In particular, tenofovir
alafenamide may be associated with fumarate, such as monofumarate
or hemifumarate. Typically, tenofovir alafenamide is in the form of
tenofovir alafenamide hemifumarate having the formula below (see WO
2013/025788 A1):
##STR00007##
[0043] As used herein, and in the absence of a specific reference
to a particular pharmaceutically acceptable salt and/or solvate of
tenofovir alafenamide, any dosages, whether expressed in e.g.
milligrams or as a % by weight, should be taken as referring to the
amount of tenofovir alafenamide, i.e. the amount of:
##STR00008##
[0044] For example, therefore, a reference to "25 mg tenofovir
alafenamide or a pharmaceutically acceptable salt and/or solvate
thereof" means an amount of tenofovir alafenamide or a
pharmaceutically acceptable salt and/or solvate thereof which
provides the same amount of tenofovir alafenamide as 25 mg of
tenofovir alafenamide free base.
[0045] The amount of tenofovir alafenamide in a solid oral dosage
form provided herein is generally between 10 mg and 30 mg, for
instance within the range of 20 mg to 30 mg, and more typically
between 24 mg and 28 mg. In certain specific embodiments, solid
oral dosage forms containing 25 mg of tenofovir alafenamide e.g. as
about 28 mg of tenofovir alafenamide hemifumarate, are
provided.
Emtricitabine
[0046] Emtricitabine (FTC) is a nucleoside reverse transcriptase
inhibitor having the formula below:
##STR00009##
[0047] Its IUPAC name is
4-amino-5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-di-
hydropyrimidin-2-one. It is also referred to as
5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine.
It is currently authorised as part of EMTRIVA.RTM. (emtricitabine
200 mg), TRUVADA.RTM. (emtricitabine 200 mg, tenofovir disoproxil
fumarate 300 mg), ATRIPLA.RTM. (emtricitabine 200 mg, efavirenz 600
mg, tenofovir disoproxil fumarate 300 mg) and STRIBILD.RTM.
(emtricitabine 200 mg, cobicistat 150 mg, tenofovir disoproxil
fumarate 300 mg, elvitegravir 150 mg) and
COMPLERA.RTM./EVIPLERA.RTM. (rilpivirine 25 mg, emtricitabine 200
mg, tenofovir disoproxil fumarate 300 mg).
[0048] Emtricitabine is a free base, exhibiting a pKa of 2.65.
Solubility is enhanced under acidic conditions. It is considered a
BCS Class 1 compound, with high solubility and high
permeability.
[0049] Solid oral dosage forms disclosed herein include
emtricitabine, optionally as a pharmaceutically acceptable salt.
Emtricitabine can be present within an oral dosage form in solvated
or unsolvated form, and references to "emtricitabine" include both
of these forms. Typically, emtricitabine is present as a free
base.
[0050] As used herein, and in the absence of a specific reference
to a particular pharmaceutically acceptable salt and/or solvate of
emtricitabine, any dosages, whether expressed in e.g. milligrams or
as a % by weight, should be taken as referring to the amount of
emtricitabine, i.e. the amount of:
##STR00010##
[0051] For example, therefore, a reference to "200 mg emtricitabine
or a pharmaceutically acceptable salt and/or solvate thereof" means
an amount of emtricitabine or a pharmaceutically acceptable salt
and/or solvate thereof which provides the same amount of
emtricitabine as 200 mg of emtricitabine free base.
[0052] The amount of emtricitabine in a solid oral dosage form
provided herein is generally between 180 mg and 220 mg, for
instance between 190 mg and 210 mg, and more typically between 195
mg and 205 mg. In certain specific embodiments, solid oral dosage
forms containing 200 mg of emtricitabine are provided.
Solid Oral Dosage Forms
[0053] The inventors have successfully formulated the compound of
Formula I, emtricitabine and tenofovir alafenamide in a single,
stable dosage form that is pharmacologically efficacious and
physically acceptable. The solid oral dosage forms disclosed herein
are intended for pharmaceutical use in human subjects. Accordingly,
they must be of an appropriate size and weight for oral human
administration (e.g. they should have a total weight of less than
about 1.5 g, e.g., less than about 1.0 g), in addition to being
therapeutically efficacious.
[0054] In certain embodiments, formulations of the three active
ingredients into a solid oral dosage form which has a total weight
of less than about 1.0 g are provided, for instance less than about
800 mg, or even less than about 750 mg, or even less than 700 mg.
This is advantageous given that TRIUMEQ.RTM. (abacavir sulfate
equivalent to 600 mg of abacavir, dolutegravir sodium equivalent to
50 mg of dolutegravir, and 300 mg of lamivudine) has a total weight
of more than about 1000 mg, based on the weight of the active
ingredients in each tablet (due to the amount of excipients that
are required to produce a pharmaceutically acceptable tablet). The
provision of a relatively small dosage form (in particular a
tablet) represents a clinical advantage because it may be expected
to increase patient convenience and thus compliance as compared to
larger dosage forms which are more burdensome for patients to
swallow. In specific embodiments, the solid oral dosage form
disclosed herein has a total weight of between 700 and 750 mg. In
certain embodiments, the solid oral dosage form disclosed herein
has a total weight of between 700 and 725 mg, or about 700 mg. In
specific embodiments, the solid oral dosage form disclosed herein
has a total weight of between about 50 and about 750 mg, between
about 100 and about 750 mg, between about 200 and about 750 mg, or
between about 250 and about 750 mg. The presently disclosed dosage
forms may comprise less than 600 mg of excipients, such as less
than 500 mg of excipients, or less than 450 mg of excipients. For
example, solid oral dosage forms disclosed herein may comprise
between 300 and 600 mg of excipients, or between 350 mg and 500 mg
of excipients, or between 400 mg and 500 mg of excipients. Most
typically, solid oral dosage forms disclosed herein comprise
between 425 mg and 450 mg of excipients. In such embodiments, the
dosage forms comprise as active ingredients (a) 50 mg of the
compound of Formula I or a pharmaceutically acceptable salt
thereof, (b) 25 mg tenofovir alafenamide or a pharmaceutically
acceptable salt thereof, and (c) 200 mg emtricitabine or a
pharmaceutically acceptable salt thereof. In certain embodiments,
the dosage forms comprise as active ingredients (a) 52 mg of the
compound of Formula II, (b) 28 mg tenofovir alafenamide
hemifumarate, and (c) 200 mg emtricitabine. In some embodiments,
the dosage forms comprise as active ingredients (a) 75 mg of the
compound of Formula I or a pharmaceutically acceptable salt
thereof, (b) 25 mg tenofovir alafenamide or a pharmaceutically
acceptable salt thereof, and (c) 200 mg emtricitabine or a
pharmaceutically acceptable salt thereof. In certain embodiments,
the dosage forms comprise as active ingredients (a) 78 mg of the
compound of Formula II, (b) 28 mg tenofovir alafenamide
hemifumarate, and (c) 200 mg emtricitabine.
[0055] The solid oral dosage forms disclosed herein will typically
be in the form of a fixed dose combination tablet. This is because
the inventors have found that the use of fixed dose combination
tablets may assist in optimizing the pharmacokinetic properties of
the active ingredients, particularly the total exposure of the
compound of Formula I or a pharmaceutically acceptable salt
thereof, as measured by area under the curve (AUC) and C.sub.max.
In particular embodiments, the solid oral dosage forms disclosed
herein are in the form of a multilayer tablet. In certain
embodiments, the use of a fixed dose combinations, e.g., multilayer
tablets, may affect the dissolution profile of one or more of the
active ingredients within the dosage form, and is therefore likely
to have an impact on the in vivo pharmacokinetics of the dosage
form. In particular, it has been observed that the dissolution of
the compound of Formula I (e.g., as Formula II) varies depending on
whether the tablet is in a fixed dose combination formulation with
tenofovir alafenamide and emtricitabine and/or whether the tablet
is a monolayer or multilayer tablet. It has also been observed that
the presence of certain excipients in the multilayer tablet
formulation (or absence of others) affects the dissolution profile
of one or more of the active ingredients within the dosage form.
The provision of a tablet with particular pharmacokinetic
parameters, e.g. pharmacokinetic parameters is a particular
advantage afforded by the present disclosure.
[0056] In one embodiment, a multilayer tablet comprising (a) the
compound of Formula I or a pharmaceutically acceptable salt
thereof, (b) tenofovir alafenamide or a pharmaceutically acceptable
salt thereof, and (c) emtricitabine or a pharmaceutically
acceptable salt thereof is provided. Typically, each layer contains
at least one of (a), (b), and (c). For instance, in certain
embodiments, the tablet comprises a first layer comprising (a) the
compound of Formula I or a pharmaceutically acceptable salt
thereof, and a second layer comprising (b) tenofovir alafenamide or
a pharmaceutically acceptable salt thereof, and further comprises
(c) emtricitabine or a pharmaceutically acceptable salt thereof. In
such embodiments, typically the first layer is substantially free
of tenofovir alafenamide or a pharmaceutically acceptable salt
thereof, and/or the second layer is substantially free of the
compound of Formula I or a pharmaceutically acceptable salt
thereof. In one embodiment the first layer is substantially free of
tenofovir alafenamide or a pharmaceutically acceptable salt thereof
(e.g. the first layer contains less than 1% by weight tenofovir
alafenamide or a pharmaceutically acceptable salt thereof), and the
second layer is substantially free of the compound of Formula I or
a pharmaceutically acceptable salt thereof (e.g. the second layer
contains less than 1% by weight of the compound of Formula I or a
pharmaceutically acceptable salt thereof).
[0057] A particular embodiment provides a tablet, wherein the first
layer comprises the compound of Formula I or a pharmaceutically
acceptable salt thereof (e.g., Formula II) and is substantially
free of tenofovir alafenamide or a pharmaceutically acceptable salt
thereof (e.g., the first layer contains less than 1% by weight
tenofovir alafenamide or a pharmaceutically acceptable salt
thereof), and the second layer comprises tenofovir alafenamide or a
pharmaceutically acceptable salt thereof and emtricitabine or a
pharmaceutically acceptable salt thereof and is substantially free
of the compound of Formula I or a pharmaceutically acceptable salt
thereof (e.g. the second layer contains less than 1% by weight of
the compound of Formula I or a pharmaceutically acceptable salt
thereof). In a particular embodiment, a tablet is provided, wherein
the first layer comprises 52 mg of the compound of Formula II and
is substantially free of tenofovir alafenamide or a
pharmaceutically acceptable salt thereof (e.g., the first layer
contains less than 1% by weight tenofovir alafenamide or a
pharmaceutically acceptable salt thereof), and the second layer
comprises 28 mg tenofovir alafenamide hemifumarate and 200 mg
emtricitabine and is substantially free of the compound of Formula
I or a pharmaceutically acceptable salt thereof (e.g., the second
layer contains less than 1% by weight of the compound of Formula I
or a pharmaceutically acceptable salt thereof), wherein the first
layer has a total weight of less than about 400 mg, such as about
325 mg, and the second layer has a total weight of less than about
450 mg, such as about 380 mg. In one embodiment, the layer
containing tenofovir alafenamide or a pharmaceutically acceptable
salt thereof does not contain lactose and/or starch. In one
embodiment, the layer containing the compound of Formula I or a
pharmaceutically acceptable salt thereof does not contain lactose,
crospovidone and/or sodium stearyl fumarate.
[0058] A particular embodiment provides a tablet, wherein the first
layer comprises the compound of Formula I or a pharmaceutically
acceptable salt thereof (e.g., Formula II) and is substantially
free of emtricitabine or a pharmaceutically acceptable salt thereof
(e.g., the first layer contains less than 1% by weight
emtricitabine or a pharmaceutically acceptable salt thereof), and
(b) the second layer comprises tenofovir alafenamide or a
pharmaceutically acceptable salt thereof and emtricitabine or a
pharmaceutically acceptable salt thereof and is substantially free
of the compound of Formula I or a pharmaceutically acceptable salt
thereof (e.g. the second layer contains less than 1% by weight of
the compound of Formula I or a pharmaceutically acceptable salt
thereof). In a particular embodiment, a tablet is provided, wherein
(a) the first layer comprises 52 mg of the compound of Formula II
and is substantially free of emtricitabine or a pharmaceutically
acceptable salt thereof (e.g., the first layer contains less than
1% by weight emtricitabine or a pharmaceutically acceptable salt
thereof), and (b) the second layer comprises 28 mg tenofovir
alafenamide hemifumarate and 200 mg emtricitabine and is
substantially free of the compound of Formula I or a
pharmaceutically acceptable salt thereof (e.g., the second layer
contains less than 1% by weight of the compound of Formula I or a
pharmaceutically acceptable salt thereof), wherein the first layer
has a total weight of less than about 400 mg, such as about 325 mg,
and the second layer has a total weight of less than about 450 mg,
such as about 380 mg. In one embodiment, the layer containing
emtricitabine or a pharmaceutically acceptable salt thereof does
not contain lactose and/or starch. In one embodiment, the layer
containing the compound of Formula I or a pharmaceutically
acceptable salt thereof does not contain lactose, crospovidone
and/or sodium stearyl fumarate.
[0059] A particular embodiment provides a tablet, wherein the first
layer comprises the compound of Formula I or a pharmaceutically
acceptable salt thereof (e.g., Formula II) and is substantially
free of tenofovir alafenamide and emtricitabine or a
pharmaceutically acceptable salt thereof (e.g., the first layer
contains less than 1% by weight each of tenofovir alafenamide and
emtricitabine or a pharmaceutically acceptable salt thereof), and
(b) the second layer comprises tenofovir alafenamide or a
pharmaceutically acceptable salt thereof and emtricitabine or a
pharmaceutically acceptable salt thereof and is substantially free
of the compound of Formula I or a pharmaceutically acceptable salt
thereof (e.g. the second layer contains less than 1% by weight of
the compound of Formula I or a pharmaceutically acceptable salt
thereof). In a particular embodiment, a tablet is provided, wherein
(a) the first layer comprises 52 mg of the compound of Formula II
and is substantially free of tenofovir alafenamide and
emtricitabine or a pharmaceutically acceptable salt thereof (e.g.,
the first layer contains less than 1% by weight tenofovir
alafenamide and emtricitabine or a pharmaceutically acceptable salt
thereof), and (b) the second layer comprises 28 mg tenofovir
alafenamide hemifumarate and 200 mg emtricitabine and is
substantially free of the compound of Formula I or a
pharmaceutically acceptable salt thereof (e.g., the second layer
contains less than 1% by weight of the compound of Formula I or a
pharmaceutically acceptable salt thereof), wherein the first layer
has a total weight of less than about 400 mg, such as about 325 mg,
and the second layer has a total weight of less than about 450 mg,
such as about 380 mg. In one embodiment, the layer containing
tenofovir alafenamide and emtricitabine or a pharmaceutically
acceptable salt thereof does not contain lactose and/or starch. In
one embodiment, the layer containing the compound of Formula I or a
pharmaceutically acceptable salt thereof does not contain lactose,
crospovidone and/or sodium stearyl fumarate.
[0060] In a particular embodiment, a tablet is provided, wherein
(a) the first layer comprises 78 mg of the compound of Formula II
and is substantially free of tenofovir alafenamide or a
pharmaceutically acceptable salt thereof (e.g. the first layer
contains less than 1% by weight tenofovir alafenamide or a
pharmaceutically acceptable salt thereof), and (b) the second layer
comprises 28 mg tenofovir alafenamide hemifumarate and 200 mg
emtricitabine and is substantially free of the compound of Formula
I or a pharmaceutically acceptable salt thereof (e.g. the second
layer contains less than 1% by weight of the compound of Formula I
or a pharmaceutically acceptable salt thereof), wherein the first
layer has a total weight of less than about 400 mg, such as about
355 mg, and the second layer has a total weight of less than about
450 mg, such as about 380 mg. In one embodiment, the layer
containing tenofovir alafenamide or a pharmaceutically acceptable
salt thereof does not contain lactose and/or starch.
[0061] Unless otherwise specified, the terms "first layer", "second
layer", "third layer" and so forth do not specify a particular
order or orientation of the multilayer tablet formulations
disclosed herein. Rather, these terms are used to distinguish the
sections of the composition from each other and to specify the
characteristics or components of each section or compartment. By
way of example, in an embodiment, a tablet is provided wherein a
first layer comprises 52 mg of the compound of Formula II and is
substantially free of tenofovir alafenamide or a pharmaceutically
acceptable salt thereof (e.g., the first layer contains less than
1% by weight tenofovir alafenamide or a pharmaceutically acceptable
salt thereof), and (b) the second layer comprises 28 mg tenofovir
alafenamide hemifumarate and 200 mg emtricitabine and is
substantially free of the compound of Formula I or a
pharmaceutically acceptable salt thereof (e.g., the second layer
contains less than 1% by weight of the compound of Formula I or a
pharmaceutically acceptable salt thereof), wherein the first layer
has a total weight of less than about 400 mg, such as about 325 mg,
and the second layer has a total weight of less than about 450 mg,
such as about 380 mg. The first layer may be synthesized first or
may be synthesized second. The first layer may be on the bottom or
may be on the top or may be on a side. The term "first layer" is
not limiting as to order and orientation.
[0062] The tablets disclosed herein are typically immediate release
tablets. In one embodiment, a tablet is provided which releases at
least 50% of the compound of Formula I or a pharmaceutically
acceptable salt thereof in about 20 minutes, measured using USP
apparatus II, in 333 mL of fasted state simulated intestinal fluid,
pH 6.5, at 37.degree. C. and paddle speed of 100 rpm. In certain
embodiments, the tablets disclosed herein release at least 60% of
the compound of Formula I or a pharmaceutically acceptable salt
thereof in 20 minutes, measured using USP apparatus II, in 333 mL
of 50 mM fasted state simulated intestinal fluid, at 37.degree. C.
and paddle speed of 100 rpm. In some embodiments, a tablet that
releases at least 70% of the compound of Formula I in 60 minutes is
provided, measured using USP Apparatus II, in 333 mL of fasted
state simulated intestinal fluid at 37.degree. C. and paddle speed
of 100 rpm.
[0063] Tablets disclosed herein will generally have a hardness
within the range 14-20 kP, and, in certain specific embodiments,
have a hardness of 17 kP. Hardness can conveniently be assessed by
driving an anvil to compress a tablet at a constant loading rate
until it fractures, operating in accordance with USP <1217>
(using e.g. a TBH 220, ERWEKA GmbH, Heusenstamm Germany hardness
tester).
[0064] Tablets disclosed herein will generally have a friability of
<1% by weight. Friability can be assessed according to USP
<1216>.
[0065] The core of a tablet provided herein may have a hardness of
between 14-20 kP, and a friability of <1% by weight.
[0066] Tablets will typically include one or more excipients.
Excipients should be compatible with the other ingredients of the
formulation and physiologically innocuous to the recipient thereof.
Examples of suitable excipients are well known to the person
skilled in the art of tablet formulation and may be found e.g. in
Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey &
Quinn), 6th edition 2009. As used herein the term "excipients" is
intended to refer to inter alia basifying agents, solubilisers,
glidants, fillers, binders, lubricant, diluents, preservatives,
surface active agents, dispersing agents and the like. The term
also includes agents such as sweetening agents, flavoring agents,
coloring agents, preserving agents, and coating agents. Such
components will generally be present in admixture within the
tablet.
[0067] Examples of solubilisers include, but are not limited to,
ionic surfactants (including both ionic and non-ionic surfactants)
such as sodium lauryl sulphate, cetyltrimethylammonium bromide,
polysorbates (such as polysorbate 20 or 80), poloxamers (such as
poloxamer 188 or 207), and macrogols. In a particular embodiment, a
tablet that comprises the compound of Formula I or a
pharmaceutically acceptable salt thereof, includes a polysorbate,
in particular polysorbate 20. In certain specific embodiments, the
amount of polysorbate 20 in a tablet disclosed herein is less than
about 5 mg, such as less than about 1 mg, or about 0.5 mg.
[0068] 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. The amount of lubricant in a tablet is generally
between about 0.5-5% by weight. In certain embodiments, the amount
of lubricant in a tablet is about 1.5% by weight. In certain
specific embodiments, tablets disclosed herein include magnesium
stearate. In certain other embodiments, the tablets disclosed
herein do not include sodium stearyl fumarate. In certain
embodiments, the tablet includes less than about 10 mg magnesium
stearate, or less than about 7.5 mg magnesium stearate. In certain
embodiments, the tablet includes less than about 9 mg magnesium
stearate, or less than about 8.75 mg magnesium stearate. In certain
embodiments, the tablet includes about 5 mg to about 10 mg
magnesium stearate, or about 6 mg to about 9 mg magnesium stearate,
or about 7 mg to about 9 mg magnesium stearate, or about 8 mg to
about 9 mg magnesium stearate, or about 8.1 mg, about 8.2 mg, about
8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg,
about 8.8 mg or about 8.9 mg magnesium stearate.
[0069] Examples of disintegrants include, but are not limited to,
starches, celluloses, cross-linked PVP (crospovidone), sodium
starch glycolate, croscarmellose sodium, etc. In certain
embodiments, the tablets disclosed herein include croscarmellose
sodium. In certain other embodiments, the tablets disclosed herein
do not include crospovidone. In certain embodiments, the tablet
includes less than about 50 mg croscarmellose sodium, or less than
about 25 mg croscarmellose sodium. In certain embodiments, the
tablet includes about 30 mg to about 60 mg croscarmellose sodium,
or about 40 mg to about 60 mg croscarmellose sodium, or about 45 mg
to about 55 mg croscarmellose sodium, or about 45 mg, about 46 mg,
about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg,
about 52 mg or about 53 mg, or about 54 mg, or about 55 mg
croscarmellose sodium.
[0070] Examples of fillers (also known as bulking agents or
diluents) include, but are not limited to, starches, maltodextrins,
polyols (such as lactose), and celluloses. In certain embodiments,
tablets provided herein may microcrystalline cellulose. In certain
other embodiments, tablets provided herein do not contain lactose.
In certain embodiments, tablets provided herein include less than
about 300 mg microcrystalline cellulose, in particular less than
about 250 mg microcrystalline cellulose, and/or less than about 225
mg microcrystalline cellulose. In certain embodiments, tablets
provided herein include less than about 500 mg microcrystalline
cellulose, or less than about 450 mg microcrystalline cellulose, or
less than about 400 mg microcrystalline cellulose, or less than
about 375 mg microcrystalline cellulose. In certain embodiments,
tablets provided herein include about 250 mg to about 500 mg
microcrystalline cellulose, or about 300 mg to about 450 mg
microcrystalline cellulose, or about 300 mg to about 400 mg
microcrystalline cellulose, or about 325 mg to about 375 mg
microcrystalline cellulose, or about 350 mg to about 370 mg
microcrystalline cellulose. In certain embodiments, tablets
provided herein include about 300 mg, or about 310 mg, or about 320
mg, or about 330 mg, or about 340 mg, or about 350 mg, or about 360
mg, or about 370 mg, or about 380 mg, or about 390 mg, or about 400
mg microcrystalline cellulose.
[0071] Examples of binders include, but are not limited to,
cross-linked PVP, HPMC, sucrose, starches, etc.
[0072] In certain embodiments, tablets provided herein are
uncoated. In certain other embodiments, tablets provided herein are
coated (in which case they include a coating). Although uncoated
tablets may be used, it is more usual in the clinical setting to
provide a coated tablet, in which case a conventional non-enteric
coating may be used. 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. Though in certain
embodiments the water soluble material included in the film coating
of the embodiments disclosed herein includes a single polymer
material, in certain other embodiments it is formed using a mixture
of more than one polymer. In certain embodiments, the coating is
yellow or brown. Suitable coatings include, but are not limited to,
polymeric film coatings such as those comprising polyvinyl alcohol
e.g. `Opadry.RTM. II` (which includes part-hydrolysed PVA, titanium
dioxide, macrogol 3350 (PEG) and talc, with optional colouring such
as iron oxide (e.g., iron oxide red or iron oxide black) or indigo
carmine or iron oxide yellow or FD&C yellow #6). The amount of
coating is generally between about 2-4% of the core's weight, and
in certain specific embodiments, about 3%. Unless specifically
stated otherwise, where the dosage form is coated, it is to be
understood that a reference to % weight of the tablet means that of
the total tablet, i.e. including the coating.
Pharmacokinetics
[0073] In certain embodiments, the pharmaceutical compositions
disclosed herein result in increased systemic exposure
(AUC.sub.inf, C.sub.max) for the compound of Formula I or a
pharmaceutically acceptable salt thereof. In particular
embodiments, the multilayer tablet formulations disclosed herein
result in increased systemic exposure for the compound of Formula I
or a pharmaceutically acceptable salt thereof compared to a single
agent tablet formulation of the compound of Formula I or a
pharmaceutically acceptable salt thereof. In certain embodiments,
the multilayer tablet formulation results in an increase of at
least about 20% in the systemic exposure of the compound of Formula
I or a pharmaceutically acceptable salt thereof compared to a
single agent tablet formulation of the compound of Formula I or a
pharmaceutically acceptable salt thereof. In some embodiments, the
increase in systemic exposure is at least about 25% or at least
about 30%. In some embodiments, the increase in systemic exposure
is about 30%.
C.sub.max
[0074] C.sub.max is the maximum observed plasma/serum concentration
of drug.
[0075] In particular embodiments, a pharmaceutical composition
comprising a tablet containing 75 mg of the compound of Formula I
or a pharmaceutically acceptable salt thereof, 200 mg emtricitabine
or a pharmaceutically acceptable salt thereof, and 25 mg tenofovir
alafenamide or a pharmaceutically acceptable salt thereof provide a
plasma C.sub.max of the compound of Formula I in fasted patients of
from about 5300 to about 8900 ng/mL, e.g. about 7100 ng/mL.
[0076] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 75 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma C.sub.max of emtricitabine in fasted
patients of from about 1700 to about 2800 ng/mL, e.g. about 2300
ng/mL.
[0077] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 75 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma C.sub.max of tenofovir alafenamide in
fasted patients of from about 190 to about 320 ng/mL, e.g. about
250 ng/mL.
[0078] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma C.sub.max of the Compound of Formula I of
from about from about 4200 ng/mL to about 8000 ng/mL, regardless of
whether the subject was fed or fasted.
[0079] In particular embodiments, a pharmaceutical composition
comprising a tablet containing 50 mg of the compound of Formula I
or a pharmaceutically acceptable salt thereof, 200 mg emtricitabine
or a pharmaceutically acceptable salt thereof, and 25 mg tenofovir
alafenamide or a pharmaceutically acceptable salt thereof provide a
plasma C.sub.max of the compound of Formula I in fasted patients of
from about 4200 ng/mL to about 6500 ng/mL, or from about 4700 ng/mL
to about 5300 ng/mL, or from about 4700 ng/mL to about 5800 ng/mL,
or from about 5000 ng/mL to about 5500 ng/mL.
[0080] In particular embodiments, a pharmaceutical composition
comprising a tablet containing 50 mg of the compound of Formula I
or a pharmaceutically acceptable salt thereof, 200 mg emtricitabine
or a pharmaceutically acceptable salt thereof, and 25 mg tenofovir
alafenamide or a pharmaceutically acceptable salt thereof provide a
plasma C.sub.max of the compound of Formula I in fed patients of
from about 4500 ng/mL to about 8000 ng/mL, or from about 4800 ng/mL
to about 7900 ng/mL, or from about 5300 ng/mL to about 6900 ng/mL,
or from about 5600 ng/mL to about 6600 ng/mL.
[0081] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma C.sub.max of emtricitabine of from about
from about 1770 ng/mL to about 2800 ng/mL, regardless of whether
the subject was fed or fasted.
[0082] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma C.sub.max of emtricitabine in fasted
patients of from about 1770 ng/mL to about 2800 ng/mL, or from
about 2000 ng/mL to about 2600 ng/mL, or from about 2000 ng/mL to
about 2500 ng/mL, or from about 2100 ng/mL to about 2400 ng/mL.
[0083] In particular embodiments, a pharmaceutical composition
comprising a tablet containing 50 mg of the compound of Formula I
or a pharmaceutically acceptable salt thereof, 200 mg emtricitabine
or a pharmaceutically acceptable salt thereof, and 25 mg tenofovir
alafenamide or a pharmaceutically acceptable salt thereof provide a
plasma C.sub.max of emtricitabine in fed patients of from about
1000 ng/mL to about 3000 ng/mL, or from about 1500 ng/mL to about
2000 ng/m from about 1700 ng/mL to about 2200 ng/mL L, or from
about 1800 ng/mL to about 2100 ng/mL.
[0084] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma C.sub.max of tenofovir alafenamide of from
about from about 185 ng/mL to about 315 ng/mL, regardless of
whether the subject was fed or fasted.
[0085] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma C.sub.max of tenofovir alafenamide in
fasted patients of from about 185 ng/mL to about 315 ng/mL, or from
about 200 ng/mL to about 300 ng/mL, or from about 210 ng/mL to
about 290 ng/mL, or from about 220 ng/mL to about 275 ng/mL, or
from about 230 ng/mL to about 265 ng/mL, or from about 240 ng/mL to
about 260 ng/mL.
[0086] In particular embodiments, a pharmaceutical composition
comprising a tablet containing 50 mg of the compound of Formula I
or a pharmaceutically acceptable salt thereof, 200 mg emtricitabine
or a pharmaceutically acceptable salt thereof, and 25 mg tenofovir
alafenamide or a pharmaceutically acceptable salt thereof provide a
plasma C.sub.max of tenofovir alafenamide in fed patients of from
about 150 ng/mL to about 350 ng/mL, or from about 185 ng/mL to
about 300 ng/m from about 210 ng/mL to about 280 ng/mL L, or from
about 250 ng/mL to about 265 ng/mL.
AUC.sub.inf
[0087] AUC.sub.inf is the area under the plasma/serum concentration
versus time curve extrapolated to infinite time, calculated as
AUC.sub.0-last+(C.sub.last/.lamda..sub.z).
[0088] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 75 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.inf of the compound of Formula I
in fed patients of from about 117000 to about 196000 hng/mL, e.g.
about 157000 hng/mL.
[0089] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 75 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.inf of emtricitabine in fed
patients of from about 8700 to about 14500 hng/mL, e.g. about 2300
hng/mL.
[0090] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 75 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.inf of tenofovir alafenamide in
fed patients of from about 150 and 260 hng/mL, e.g. about 210
hng/mL.
[0091] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.inf of the Compound of Formula I
of from about from about 84450 hng/mL to about 141000 hng/mL,
regardless of whether the subject was fed or fasted.
[0092] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.inf of the compound of Formula I
in fasted patients of from about 84450 hng/mL to about 141000
hng/mL, or from about 90000 hng/mL to about 135000 hng/mL, or from
about 95000 hng/mL to about 130000 hng/mL, or from about 100000
hng/mL to about 125000 hng/mL, or from about 110000 hng/mL to about
120000 hng/mL.
[0093] In particular embodiments, a pharmaceutical composition
comprising a tablet containing 50 mg of the compound of Formula I
or a pharmaceutically acceptable salt thereof, 200 mg emtricitabine
or a pharmaceutically acceptable salt thereof, and 25 mg tenofovir
alafenamide or a pharmaceutically acceptable salt thereof provide a
plasma AUC.sub.inf of the compound of Formula I in fed patients of
from about 100000 hng/mL to about 200000 ng/mL, or from about
112000 hng/mL to about 175000 ng/mL, or from about 126000 hng/mL to
about 155000 ng/mL, or from about 133000 hng/mL to about 147000
ng/mL.
[0094] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.inf of emtricitabine of from about
from about 8100 hng/mL to about 13600 hng/mL, regardless of whether
the subject was fed or fasted.
[0095] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.inf of emtricitabine in fasted
patients of from about 8100 hng/mL to about 13600 hng/mL, or from
about 8700 hng/mL to about 13000 hng/mL, or from about 92000 hng/mL
to about 12500 hng/mL, or from about 9700 hng/mL to about 12000
hng/mL, or from about 10000 hng/mL to about 11400 hng/mL.
[0096] In particular embodiments, a pharmaceutical composition
comprising a tablet containing 50 mg of the compound of Formula I
or a pharmaceutically acceptable salt thereof, 200 mg emtricitabine
or a pharmaceutically acceptable salt thereof, and 25 mg tenofovir
alafenamide or a pharmaceutically acceptable salt thereof provide a
plasma AUC.sub.inf of emtricitabine in fed patients of from about
7500 hng/mL to about 15000 ng/mL, or from about 8300 hng/mL to
about 14000 ng/mL, or from about 9500 hng/mL to about 12000 ng/mL,
or from about 9900 hng/mL to about 11600 ng/mL.
[0097] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.inf of tenofovir alafenamide of
from about from about 200 hng/mL to about 500 hng/mL, regardless of
whether the subject was fed or fasted.
[0098] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.inf of tenofovir alafenamide in
fasted patients of from about 200 hng/mL to about 265 hng/mL, or
from about 200 hng/mL to about 300 hng/mL, or from about 210 hng/mL
to about 290 hng/mL, or from about 220 hng/mL to about 270 hng/mL,
or from about 230 hng/mL to about 265 hng/mL.
[0099] In particular embodiments, a pharmaceutical composition
comprising a tablet containing 50 mg of the compound of Formula I
or a pharmaceutically acceptable salt thereof, 200 mg emtricitabine
or a pharmaceutically acceptable salt thereof, and 25 mg tenofovir
alafenamide or a pharmaceutically acceptable salt thereof provide a
plasma AUC.sub.inf of tenofovir alafenamide in fed patients of from
about 200 hng/mL to about 500 ng/mL, or from about 230 hng/mL to
about 400 ng/mL, or from about 260 hng/mL to about 350 ng/mL, or
from about 275 hng/mL to about 370 ng/mL.
AUC.sub.last
[0100] AUC.sub.last is the area under the plasma/serum
concentration versus time curve from time zero to the last
quantifiable concentration.
[0101] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 75 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.last of the compound of Formula I
in fed patients of from about 114000 to about 190000 hng/mL, e.g.
about 152000 hng/mL.
[0102] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 75 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.last of emtricitabine in fed
patients of from about 8600 to about 14000 hng/mL, e.g. about 11000
hng/mL.
[0103] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 75 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.last of tenofovir alafenamide in
fed patients of from about 150 and 260 hng/mL, e.g. about 210
hng/mL.
[0104] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.last of the compound of Formula I
of from about from about 81700 hng/mL to about 140000 hng/mL,
regardless of whether the subject was fed or fasted.
[0105] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.last of the compound of Formula I
in fasted patients of from about 81700 hng/mL to about 140000
hng/mL, from about 87000 hng/mL to about 131000 hng/mL, from about
92000 hng/mL to about 130000 hng/mL, from about 98100 hng/mL to
about 120000 hng/mL, from about 104000 hng/mL to about 115000
hng/mL.
[0106] In particular embodiments, a pharmaceutical composition
comprising a tablet containing 50 mg of the compound of Formula I
or a pharmaceutically acceptable salt thereof, 200 mg emtricitabine
or a pharmaceutically acceptable salt thereof, and 25 mg tenofovir
alafenamide or a pharmaceutically acceptable salt thereof provide a
plasma AUC.sub.last of the compound of Formula I in fed patients of
from about 100000 hng/mL to about 200000 ng/mL, or from about
108000 hng/mL to about 170000 ng/mL, or from about 122000 hng/mL to
about 150000 ng/mL, or from about 128000 hng/mL to about 142000
ng/mL.
[0107] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.last of emtricitabine of from
about from about 7500 hng/mL to about 15000 hng/mL, regardless of
whether the subject was fed or fasted.
[0108] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.last of the emtricitabine in
fasted patients of from about 8000 hng/mL to about 13400 hng/mL,
from about 8500 hng/mL to about 12800 hng/mL, from about 9000
hng/mL to about 12300 hng/mL, from about 9500 hng/mL to about 11000
hng/mL, from about 10000 hng/mL to about 11200 hng/mL.
[0109] In particular embodiments, a pharmaceutical composition
comprising a tablet containing 50 mg of the compound of Formula I
or a pharmaceutically acceptable salt thereof, 200 mg emtricitabine
or a pharmaceutically acceptable salt thereof, and 25 mg tenofovir
alafenamide or a pharmaceutically acceptable salt thereof provide a
plasma AUC.sub.last of emtricitabine in fed patients of from about
7500 hng/mL to about 15000 ng/mL, or from about 8000 hng/mL to
about 14000 ng/mL, or from about 9000 hng/mL to about 12000 ng/mL,
or from about 9700 hng/mL to about 11300 ng/mL.
[0110] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.last of tenofovir alafenamide of
from about from about 165 hng/mL to about 400 hng/mL, regardless of
whether the subject was fed or fasted.
[0111] In certain specific embodiments, a pharmaceutical
composition comprising a tablet containing 50 mg of the compound of
Formula I or a pharmaceutically acceptable salt thereof, 200 mg
emtricitabine or a pharmaceutically acceptable salt thereof, and 25
mg tenofovir alafenamide or a pharmaceutically acceptable salt
thereof provide a plasma AUC.sub.last of the tenofovir alafenamide
in fasted patients of from about 165 hng/mL to about 390 hng/mL,
from about 186 hng/mL to about 227 hng/mL, from about 196 hng/mL to
about 217 hng/mL.
[0112] In particular embodiments, a pharmaceutical composition
comprising a tablet containing 50 mg of the compound of Formula I
or a pharmaceutically acceptable salt thereof, 200 mg emtricitabine
or a pharmaceutically acceptable salt thereof, and 25 mg tenofovir
alafenamide or a pharmaceutically acceptable salt thereof provide a
plasma AUC.sub.last of tenofovir alafenamide in fed patients of
from about 200 hng/mL to about 400 ng/mL, or from about 230 hng/mL
to about 390 ng/mL, or from about 260 hng/mL to about 345 ng/mL, or
from about 275 hng/mL to about 330 ng/mL.
C.sub.last
[0113] C.sub.last is the last observed quantifiable plasma/serum
concentration of the drug.
[0114] C.sub.max, C.sub.last, AUC.sub.inf, and AUC.sub.last are
standard pharmacokinetic parameters that can be estimated manually
or by using modelling software well known in the art, such as the
Pharsight WinNonlin package using a non-compartmental model. The
general basis for calculation of these quantities is well-known
(e.g. see Rowland & Tozer (2010) Clinical Pharmacokinetics and
Pharmacodynamics: Concepts and Applications ISBN 978-0781750097, or
Jambhekar & Breen (2012) Basic Pharmacokinetics ISBN
978-0853699804). Typically the parameters will be assessed as the
average (e.g. geometric or arithmetic mean) from within a group of
at least 12 (and normally between 24 and 36) healthy human adults.
Parameters should be measured in accordance with standards and
practices which would be acceptable to a pharmaceutical regulatory
agency such as FDA, EMA, MHLW, or WHO. The values may be based on
measurements taken at appropriate intervals following the time of
tablet ingestion, such as every hour, or at increasingly sparse
sampling intervals, such as 1, 3, 5, 7, 9, 11, 13, 15, 20, and 24
hours after ingestion. They can be assessed either following a
single-dose of drug or at steady state, but will typically be
assessed following a single-dose.
[0115] It is well known in the bioavailability and bioequivalence
arts how to determine whether any particular tablet meets
regulatory requirements for equivalent bioavailability and
pharmacokinetic bioequivalence e.g. see: Niazi (2014) Handbook of
Bioequivalence Testing, 2nd Edition, ISBN 978-1482226379; Guidance
for Industry Bioavailability and Bioequivalence Studies for Orally
Administered Drug Products--General Considerations FDA March 2003;
and Guideline On The Investigation Of Bioequivalence, EMEA 2010
CPMP/EWP/QWP/1401/98 Rev. 1/Corr **. To ensure statistical power a
study to measure the C.sub.max, AUC.sub.last and AUC.sub.inf values
will be performed in multiple subjects e.g. in a group of at least
12 (and normally between 24 and 36) healthy human adults.
[0116] Because determining the C.sub.max, AUC.sub.last and
AUC.sub.inf values is necessarily destructive these parameters will
not be determined directly for the dosage form (in particular the
tablet) in question, but rather for a dosage form made by the same
manufacturing process with the same components. Thus a batch of a
dosage form (e.g. tablets) can be made by a particular process, and
the 90% confidence interval of C.sub.max, AUC.sub.last and
AUC.sub.inf will be assessed on a sample of those tablets. If these
values meet the 80-125% requirement noted above then tablets made
by the manufacturing process in question are tablets of the present
invention.
[0117] A fixed dose combination tablet is provided comprising (a)
the compound of Formula I or a pharmaceutically acceptable salt
thereof (e.g. Formula II), (b) tenofovir alafenamide or a
pharmaceutically acceptable salt thereof, and (c) emtricitabine or
a pharmaceutically acceptable salt thereof.
[0118] In an embodiment, a multilayer tablet is provided,
comprising (a) the compound of Formula I or a pharmaceutically
acceptable salt thereof (e.g. Formula II), (b) tenofovir
alafenamide or a pharmaceutically acceptable salt thereof, and (c)
emtricitabine or a pharmaceutically acceptable salt thereof.
[0119] In an embodiment, the multilayer tablet disclosed herein
comprises (a) a first layer comprising the compound of Formula I or
a pharmaceutically acceptable salt thereof, (b) a second layer
containing tenofovir alafenamide or a pharmaceutically acceptable
salt thereof, and (c) further comprises emtricitabine or a
pharmaceutically acceptable salt thereof.
[0120] In an embodiment of the multilayer tablet disclosed herein,
(a) the first layer is substantially free of tenofovir alafenamide
or a pharmaceutically acceptable salt thereof, and/or (b) the
second layer is substantially free of the compound of Formula I or
a pharmaceutically acceptable salt thereof.
[0121] In an embodiment of the multilayer tablet disclosed herein,
(a) the first layer is substantially free of emtricitabine or a
pharmaceutically acceptable salt thereof, and/or (b) the second
layer is substantially free of the compound of Formula I or a
pharmaceutically acceptable salt thereof.
[0122] In an embodiment of the multilayer tablet disclosed herein,
(a) the first layer is substantially free of emtricitabine or a
pharmaceutically acceptable salt thereof and tenofovir alafenamide
or a pharmaceutically acceptable salt thereof, and/or (b) the
second layer is substantially free of the compound of Formula I or
a pharmaceutically acceptable salt thereof.
[0123] In an embodiment, the multilayer tablet disclosed herein
comprises (a) a first layer comprising the compound of Formula I or
a pharmaceutically acceptable salt thereof, (b) a second layer
containing emtricitabine or a pharmaceutically acceptable salt
thereof, and (c) further comprises tenofovir alafenamide or a
pharmaceutically acceptable salt thereof.
[0124] In an embodiment of the multilayer tablet disclosed herein,
(a) the first layer is substantially free of emtricitabine or a
pharmaceutically acceptable salt thereof, and/or (b) the second
layer is substantially free of the compound of Formula I or a
pharmaceutically acceptable salt thereof.
[0125] In an embodiment of the multilayer tablet disclosed herein,
(a) the first layer comprises the compound of Formula I or a
pharmaceutically acceptable salt thereof and is substantially free
of tenofovir alafenamide or a pharmaceutically acceptable salt
thereof, and (b) the second layer comprises tenofovir alafenamide
or a pharmaceutically acceptable salt thereof and emtricitabine or
a pharmaceutically acceptable salt thereof and is substantially
free of the compound of Formula I or a pharmaceutically acceptable
salt thereof.
[0126] In an embodiment of the multilayer tablet disclosed herein,
the first layer is substantially free of emtricitabine.
[0127] In one embodiment, the multilayer tablet disclosed herein
comprises 50.+-.6 mg of the compound of Formula I. In one
embodiment, the multilayer tablet disclosed herein comprises
200.+-.20 mg of emtricitabine. In one embodiment, the multilayer
tablet disclosed herein comprises 25.+-.3 mg of tenofovir
alafenamide.
[0128] In one embodiment, the multilayer tablet disclosed herein
comprises 75.+-.6 mg of the compound of Formula I. In one
embodiment, the multilayer tablet disclosed herein comprises
200.+-.20 mg of emtricitabine. In one embodiment, the multilayer
tablet disclosed herein comprises 25.+-.3 mg of tenofovir
alafenamide.
[0129] In one embodiment, the multilayer tablet disclosed herein
comprises 52.+-.6 mg of the compound of Formula II. In one
embodiment, the multilayer tablet disclosed herein comprises
200.+-.20 mg of emtricitabine. In one embodiment, the multilayer
tablet disclosed herein comprises 28.+-.3 mg of tenofovir
alafenamide hemifumarate.
[0130] In one embodiment, the multilayer tablet disclosed herein
comprises 78.+-.6 mg of the compound of Formula II. In one
embodiment, the multilayer tablet disclosed herein comprises
200.+-.20 mg of emtricitabine. In one embodiment, the multilayer
tablet disclosed herein comprises 28.+-.3 mg of tenofovir
alafenamide hemifumarate.
[0131] In one embodiment, a first layer of the multilayer tablet
disclosed herein comprises one or more excipients, for example one
or more diluents, disintegrants, binders, or lubricants.
[0132] In one embodiment, a first layer of the multilayer tablet
comprises croscarmellose sodium. In one embodiment, a first layer
of the multilayer tablet comprises croscarmellose sodium,
microcrystalline cellulose, and magnesium stearate.
[0133] In one embodiment a tablet is provided wherein less than
about 25 weight percent of a first layer is the compound of Formula
I or a pharmaceutically acceptable salt thereof. In one embodiment
a tablet is provided wherein less than about 20 weight percent of a
first layer is the compound of Formula I or a pharmaceutically
acceptable salt thereof. In one embodiment a tablet is provided
wherein less than about 16 weight percent of a first layer is the
compound of Formula I or a pharmaceutically acceptable salt
thereof. In one embodiment a tablet is provided wherein about 5 to
about 20 weight percent, or about 10 to about 18 weight percent, or
about 14 to about 18 weight percent of a first layer is the
compound of Formula I or a pharmaceutically acceptable salt
thereof. In one embodiment a tablet is provided wherein about 16
weight percent of a first layer is the compound of Formula I or a
pharmaceutically acceptable salt thereof.
[0134] In one embodiment a tablet is provided wherein the first
layer comprises 52.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 290
mg.
[0135] In one embodiment a tablet is provided wherein the first
layer comprises 52.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 300
mg.
[0136] In one embodiment a tablet is provided wherein the first
layer comprises 52.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 310
mg.
[0137] In one embodiment a tablet is provided wherein the first
layer comprises 52.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 320
mg.
[0138] In one embodiment a tablet is provided wherein the first
layer comprises 52.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 330
mg.
[0139] In one embodiment a tablet is provided wherein the first
layer comprises 52.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 340
mg.
[0140] In one embodiment a tablet is provided wherein the first
layer comprises 52.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 350
mg.
[0141] In one embodiment a tablet is provided wherein the first
layer comprises 52.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 360
mg.
[0142] In one embodiment a tablet is provided wherein the first
layer comprises 52.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 290
mg and is less than about 360 mg.
[0143] In one embodiment a tablet is provided wherein the first
layer comprises 52.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 300
mg and is less than about 350 mg.
[0144] In one embodiment a tablet is provided wherein the first
layer comprises 52.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 310
mg and is less than about 330 mg.
[0145] In one embodiment, the first layer of the multilayer tablet
has a total weight of 323.+-.75 mg, or 323.+-.25 mg, or 323.+-.10
mg, or 323 mg.
[0146] In one embodiment, the first layer of the multilayer tablet
comprises:
TABLE-US-00001 Ingredient Mass (mg) The compound of Formula I or a
salt 40-60 thereof Microcrystalline cellulose 200-400
Croscarmellose sodium 1-40 Magnesium stearate 1-10
[0147] In one embodiment, the first layer of the multilayer tablet
comprises:
TABLE-US-00002 Ingredient Mass (mg) the compound of Formula II
30-60 Microcrystalline cellulose 200-400 Croscarmellose sodium 1-40
Magnesium stearate 2-8
[0148] In one embodiment, the first layer of the multilayer tablet
comprises:
TABLE-US-00003 Ingredient Mass (mg) the compound of Formula II 50
.+-. 6 Microcrystalline cellulose 250 .+-. 20 Croscarmellose sodium
20 .+-. 5 Magnesium stearate 5 .+-. 1.5
[0149] In one embodiment, the first layer of the multilayer tablet
consists of:
TABLE-US-00004 Ingredient Mass (mg) the compound of Formula II 52
.+-. 5.6 Microcrystalline cellulose 246 .+-. 10 Croscarmellose
sodium 19 .+-. 2.5 Magnesium stearate 5 .+-. 0.75
[0150] In one embodiment, the first layer of the multilayer tablet
consists of:
TABLE-US-00005 Ingredient Mass (mg) the compound of Formula II 52
.+-. 2.8 Microcrystalline cellulose 246 .+-. 5 Croscarmellose
sodium 19 .+-. 1.75 Magnesium stearate 5 .+-. 0.5
[0151] In one embodiment, the first layer of the multilayer tablet
consists of:
TABLE-US-00006 Ingredient Mass (mg) the compound of Formula II 52.5
Microcrystalline cellulose 246.3 Croscarmellose sodium 19.4
Magnesium stearate 4.9
[0152] In one embodiment, the first layer of the multilayer tablet
includes:
TABLE-US-00007 Ingredient Mass (mg) Intergranular the compound of
Formula I or a 52.5 .+-. 1.6 pharmaceutically acceptable salt
thereof Microcrystalline cellulose 214 .+-. 7.3 Croscarmellose
sodium 19 .+-. 0.6 Magnesium stearate 2.4 .+-. 0.5 Extragranular
Microcrystalline cellulose 32 .+-. 1 Magnesium stearate 2.4 .+-.
0.5 Total layer weight 323
[0153] In one embodiment, the first layer of the multilayer tablet
includes:
TABLE-US-00008 Ingredient Mass (mg) Intergranular the compound of
Formula II 52.5 .+-. 1.6 Microcrystalline cellulose 214 .+-. 7.3
Croscarmellose sodium 19 .+-. 0.6 Magnesium stearate 2.4 .+-. 0.5
Extragranular Microcrystalline cellulose 32 .+-. 1 Magnesium
stearate 2.4 .+-. 0.5 Total layer weight 323
[0154] In one embodiment, the first layer of the multilayer tablet
consists of:
TABLE-US-00009 Ingredient Mass (mg) Intergranular the compound of
Formula II 52.5 .+-. 1.6 Microcrystalline cellulose 214 .+-. 6.4
Croscarmellose sodium 19.4 .+-. 0.6 Magnesium stearate 2.45 .+-.
0.5 Extragranular Microcrystalline cellulose 32.3 .+-. 1 Magnesium
stearate 2.45 .+-. 0.5 Total layer weight 323
[0155] In one embodiment, the first layer of the multilayer tablet
includes:
TABLE-US-00010 Ingredient Mass (mg) Intergranular the compound of
Formula I, 52.5 .+-. 1.6 or a pharmaceutically acceptable salt
therof Microcrystalline cellulose 214 .+-. 6.4 Croscarmellose
sodium 19.4 .+-. 0.6 Magnesium stearate 2.43 .+-. 0.5 Extragranular
Microcrystalline cellulose 32.3 .+-. 1 Magnesium stearate 2.43 .+-.
0.5 Total layer weight 323
[0156] In one embodiment, the first layer of the multilayer tablet
includes:
TABLE-US-00011 Ingredient Mass (mg) Intergranular the compound of
Formula II 52.5 .+-. 1.6 Microcrystalline cellulose 214 .+-. 6.4
Croscarmellose sodium 19.4 .+-. 0.6 Magnesium stearate 2.43 .+-.
0.5 Extragranular Microcrystalline cellulose 32.3 .+-. 1 Magnesium
stearate 2.43 .+-. 0.5 Total layer weight 323
[0157] In one embodiment a tablet is provided wherein less than
about 30 weight percent of the first layer is the compound of
Formula I or a pharmaceutically acceptable salt thereof. In one
embodiment a tablet is provided wherein less than about 25 weight
percent of the first layer is the compound of Formula I or a
pharmaceutically acceptable salt thereof. In one embodiment a
tablet is provided wherein less than about 22 weight percent of the
first layer is the compound of Formula I or a pharmaceutically
acceptable salt thereof. In one embodiment a tablet is provided
wherein about 15 to about 27 weight percent, or about 17 to about
25 weight percent, or about 19 to about 23 weight percent of the
first layer is the compound of Formula I or a pharmaceutically
acceptable salt thereof. In one embodiment a tablet is provided
wherein about 21 weight percent of the first layer is the compound
of Formula I or a pharmaceutically acceptable salt thereof.
[0158] In one embodiment a tablet is provided wherein the first
layer comprises 78.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 320
mg.
[0159] In one embodiment a tablet is provided wherein the first
layer comprises 78.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 330
mg.
[0160] In one embodiment a tablet is provided wherein the first
layer comprises 78.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 340
mg.
[0161] In one embodiment a tablet is provided wherein the first
layer comprises 78.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 350
mg.
[0162] In one embodiment a tablet is provided wherein the first
layer comprises 78.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 360
mg.
[0163] In one embodiment a tablet is provided wherein the first
layer comprises 78.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 370
mg.
[0164] In one embodiment a tablet is provided wherein the first
layer comprises 78.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 380
mg.
[0165] In one embodiment a tablet is provided wherein the first
layer comprises 78.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 390
mg.
[0166] In one embodiment a tablet is provided wherein the first
layer comprises 78.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 320
mg and is less than about 390 mg.
[0167] In one embodiment a tablet is provided wherein the first
layer comprises 78.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 330
mg and is less than about 380 mg.
[0168] In one embodiment a tablet is provided wherein the first
layer comprises 78.+-.2.8 mg of the compound of Formula II and
wherein the total weight of the first layer is at least about 350
mg and is less than about 360 mg.
[0169] In one embodiment, the first layer of the multilayer tablet
has a total weight of 353.+-.75 mg, or 353.+-.25 mg, or 353.+-.10
mg, or 353 mg.
[0170] In one embodiment, the first layer of the multilayer tablet
comprises:
TABLE-US-00012 Ingredient Mass (mg) The compound of Formula I or a
40-85 salt thereof Microcrystalline cellulose 200-400
Croscarmellose sodium 1-40 Magnesium stearate 1-10
[0171] In one embodiment, the first layer of the multilayer tablet
comprises:
TABLE-US-00013 Ingredient Mass (mg) The compound of Formula II
30-90 Microcrystalline cellulose 200-400 Croscarmellose sodium 1-40
Magnesium stearate 2-8
[0172] In one embodiment, the first layer of the multilayer tablet
comprises:
TABLE-US-00014 Ingredient Mass (mg) The compound of Formula II 80
.+-. 6 Microcrystalline cellulose 250 .+-. 20 Croscarmellose sodium
20 .+-. 5 Magnesium stearate 5 .+-. 1.5
[0173] In one embodiment, the first layer of the multilayer tablet
consists of:
TABLE-US-00015 Ingredient Mass (mg) The compound of Formula II 78
.+-. 5.6 Microcrystalline cellulose 250 .+-. 10 Croscarmellose
sodium 20 .+-. 2.5 Magnesium stearate 5 .+-. 0.75
[0174] In one embodiment, the first layer of the multilayer tablet
consists of:
TABLE-US-00016 Ingredient Mass (mg) the compound of Formula II 78
.+-. 2.8 Microcrystalline cellulose 247 .+-. 5 Croscarmellose
sodium 21 .+-. 1.75 Magnesium stearate 5 .+-. 0.5
[0175] In one embodiment, the first layer of the multilayer tablet
consists of:
TABLE-US-00017 Ingredient Mass (mg) the compound of Formula II 78.7
Microcrystalline cellulose 247.8 Croscarmellose sodium 21.2
Magnesium stearate 5.3
[0176] In one embodiment, the first layer of the multilayer tablet
consists of:
TABLE-US-00018 Ingredient Mass (mg) Intergranular the compound of
Formula II 78.7 Microcrystalline cellulose 212.5 Croscarmellose
sodium 21.2 Magnesium stearate 2.65 Extragranular Microcrystalline
cellulose 35.3 Magnesium stearate 2.65 Total layer weight 353
[0177] In one embodiment, the second layer of the multilayer tablet
does not comprise lactose. In one embodiment, the second layer of
the multilayer tablet does not comprise starch. In one embodiment,
the second layer of the multilayer tablet comprises neither lactose
nor starch.
[0178] In one embodiment, the second layer of the multilayer tablet
comprises one or more excipients, for example, one or more
diluents, disintegrants, binders, or lubricants.
[0179] In one embodiment, the second layer of the multilayer tablet
comprises microcrystalline cellulose and croscarmellose sodium.
[0180] In one embodiment, the second layer of the multilayer tablet
comprises microcrystalline cellulose, croscarmellose sodium and
magnesium stearate.
[0181] In one embodiment, the second layer of the multilayer tablet
comprises 20-40 mg of croscarmellose sodium. In one embodiment, the
second layer of the multilayer tablet comprises 105-125 mg of
microcrystalline cellulose. In one embodiment, the second layer of
the multilayer tablet comprises 1-8 mg of magnesium stearate.
[0182] In one embodiment, the second layer of the multilayer tablet
does not comprise lactose. In one embodiment, the second layer of
the multilayer tablet does not comprise starch. In one embodiment,
the second layer of the multilayer tablet comprises neither lactose
nor starch.
[0183] In one embodiment, the second layer of the multilayer tablet
has a total weight of less than 600 mg, or less than 500 mg, or
less than 400 mg, or less than 380 mg. In one embodiment, the
second layer of the multilayer tablet has a total weight of 377
mg.+-.50 mg or 377 mg.+-.25 mg, or 377 mg.+-.5 mg, or 377 mg.
[0184] In one embodiment, over 50% by weight of the second layer of
the multilayer tablet is emtricitabine or a salt thereof and
tenofovir alafenamide or a salt thereof. In one embodiment, over
55% by weight of the second layer of the multilayer tablet is
emtricitabine or a salt thereof and tenofovir alafenamide or a salt
thereof. In one embodiment, over 60% by weight of the second layer
of the multilayer tablet is emtricitabine or a salt thereof and
tenofovir alafenamide or a salt thereof. In one embodiment, about
55% to about 65% by weight of the second layer of the multilayer
tablet is emtricitabine or a salt thereof and tenofovir alafenamide
or a salt thereof. In one embodiment, over 60% by weight of the
second layer of the multilayer tablet is emtricitabine and
tenofovir alafenamide hemifumarate. In one embodiment, about 55% to
about 65% by weight of the second layer of the multilayer tablet is
emtricitabine and tenofovir alafenamide hemifumarate.
[0185] In one embodiment, the second layer of the multilayer tablet
contains less than 250 mg of excipients, for example less than 200
mg, or less than 150 mg.
[0186] In one embodiment, at least 50% by weight of the second
layer of the multilayer tablet is emtricitabine. In one embodiment,
at least 53% by weight of the second layer of the multilayer tablet
is emtricitabine. In one embodiment, about 45% to about 65% by
weight of the second layer of the multilayer tablet is
emtricitabine. In one embodiment, about 50% to about 60% by weight
of the second layer of the multilayer tablet is emtricitabine. In
one embodiment, about 51% to about 53% by weight of the second
layer of the multilayer tablet is emtricitabine.
[0187] In one embodiment, at least 4% by weight of the second layer
of the multilayer tablet is tenofovir alafenamide hemifumarate. In
one embodiment, at least 6% by weight of the second layer of the
multilayer tablet is tenofovir alafenamide hemifumarate. In one
embodiment, at least 7% by weight of the second layer of the
multilayer tablet is tenofovir alafenamide hemifumarate. In one
embodiment, about 5% to about 10% by weight of the second layer of
the multilayer tablet is tenofovir alafenamide hemifumarate. In one
embodiment, about 6% to about 9% by weight of the second layer of
the multilayer tablet is tenofovir alafenamide hemifumarate. In one
embodiment, about 7% to about 8% by weight of the second layer of
the multilayer tablet is tenofovir alafenamide hemifumarate. In one
embodiment, about 7% by weight of the second layer of the
multilayer tablet is tenofovir alafenamide hemifumarate.
[0188] In one embodiment, less than 20% by weight of the second
layer of the multilayer tablet is croscarmellose sodium. In one
embodiment, less than 10% by weight of the second layer of the
multilayer tablet is croscarmellose sodium. In one embodiment,
about 5% to about 10% by weight of the second layer of the
multilayer tablet is croscarmellose sodium. In certain embodiments,
the use of about 5 to 7% (e.g. about 6%) croscarmellose sodium by
weight of the second layer may provide enhanced dissolution of the
compound of Formula I or a pharmaceutically acceptable salt
thereof, relative to other disintegrants e.g. polyvinylpyrrolidone
(crospovidone). In certain embodiments, the use of about 5 to 10%
croscarmellose sodium by weight of the second layer may provide
enhanced dissolution of the compound of Formula I or a
pharmaceutically acceptable salt thereof, relative to other
disintegrants e.g. polyvinylpyrrolidone (crospovidone).
[0189] In one embodiment, less than 50% by weight of the second
layer of the multilayer tablet is microcrystalline cellulose. In
one embodiment, less than 40% by weight of the second layer of the
multilayer tablet is microcrystalline cellulose. In one embodiment,
less than 31% by weight of the second layer of the multilayer
tablet is microcrystalline cellulose.
[0190] In one embodiment, less than 5% by weight of the second
layer of the multilayer tablet is magnesium stearate. In one
embodiment, less than 3% by weight of the second layer of the
multilayer tablet is magnesium stearate. In one embodiment, less
than 2% by weight of the second layer of the multilayer tablet is
magnesium stearate. In one embodiment, about 0.5% to about 1.5% by
weight of the second layer of the multilayer tablet is magnesium
stearate. In certain embodiments, the use of about 1% to about 2%
(e.g. about 1.5%) magnesium stearate by weight of the second layer
may provide enhanced dissolution of the compound of Formula I or a
pharmaceutically acceptable salt thereof, relative to other
lubricants e.g. sodium stearyl fumarate.
[0191] In one embodiment, the total weight of the second layer is
less than 150% of the total weight of the first layer. In one
embodiment, the total weight of the second layer is less than 125%
of the total weight of the first layer. In one embodiment, the
total weight of the second layer is less than 116% of the total
weight of the first layer. In one embodiment, the total weight of
the second layer is less than 106% of the total weight of the first
layer.
[0192] In one embodiment, the second layer of the multilayer tablet
comprises:
TABLE-US-00019 Ingredient Mass (mg) Emtricitabine or a salt thereof
150-250 Tenofovir alafenamide or a salt thereof 20-35
Microcrystalline cellulose 90-130 Croscarmellose sodium 20-35
Magnesium stearate 1-7
[0193] In one embodiment, the second layer of the multilayer tablet
comprises:
TABLE-US-00020 Ingredient Mass (mg) Emtricitabine 170-230 Tenofovir
alafenamide hemifumarate 22-32 Microcrystalline cellulose 100-120
Croscarmellose sodium 20-35 Magnesium stearate 1-7
[0194] In one embodiment, the second layer of the multilayer tablet
consists of:
TABLE-US-00021 Ingredient Mass (mg) Emtricitabine 200 .+-. 20
Tenofovir alafenamide hemifumarate 28 .+-. 3 Microcrystalline
cellulose 113 .+-. 9 Croscarmellose sodium 30 .+-. 3 Magnesium
stearate 5.6 .+-. 1.1
[0195] In one embodiment, the second layer of the multilayer tablet
consists of:
TABLE-US-00022 Ingredient Mass (mg) Emtricitabine 200 .+-. 10
Tenofovir alafenamide hemifumarate 28 .+-. 1.4 Microcrystalline
cellulose 113 .+-. 4 Croscarmellose sodium 30 .+-. 1.4 Magnesium
stearate 5.6 .+-. 0.5
[0196] In one embodiment, the second layer of the multilayer tablet
consists of:
TABLE-US-00023 Ingredient Mass (mg) Emtricitabine 200 Tenofovir
alafenamide hemifumarate 28.1 Microcrystalline cellulose 113.2
Croscarmellose sodium 30.2 Magnesium stearate 5.7
[0197] In one embodiment, the second layer of the multilayer tablet
consists of:
TABLE-US-00024 Ingredient Mass (mg) Intergranular Emtricitabine
200.00 Tenofovir alafenamide hemifumarate 28.1 Microcrystalline
cellulose 113.2 Croscarmellose sodium 30.2 Magnesium stearate 2.85
Extragranular Magnesium stearate 2.85 Total layer weight 377
[0198] In one embodiment, the second layer of the multilayer tablet
includes:
TABLE-US-00025 Ingredient Mass (mg) Emtricitabine 200 .+-. 20
Tenofovir alafenamide 25 .+-. 3 Microcrystalline cellulose 115 .+-.
9 Croscarmellose sodium 30 .+-. 3 Magnesium stearate 3.8 .+-.
1.1
[0199] In one embodiment, the second layer of the multilayer tablet
includes:
TABLE-US-00026 Ingredient Mass (mg) Emtricitabine 200 .+-. 20
Tenofovir alafenamide hemifumarate 28 .+-. 3 Microcrystalline
cellulose 115 .+-. 9 Croscarmellose sodium 30 .+-. 3 Magnesium
stearate 3.8 .+-. 1.1
[0200] In one embodiment, the second layer of the multilayer tablet
includes:
TABLE-US-00027 Ingredient Mass (mg) Emtricitabine 200 .+-. 10
Tenofovir alafenamide hemifumarate 28 .+-. 1.4 Microcrystalline
cellulose 115 .+-. 4 Croscarmellose sodium 30 .+-. 1.4 Magnesium
stearate 3.8 .+-. 0.5
[0201] In one embodiment, the second layer of the multilayer tablet
includes:
TABLE-US-00028 Ingredient Mass (mg) Emtricitabine 200 Tenofovir
alafenamide hemifumarate 28.1 Microcrystalline cellulose 115
Croscarmellose sodium 30.2 Magnesium stearate 3.8
[0202] In one embodiment, the second layer of the multilayer tablet
includes:
TABLE-US-00029 Ingredient Mass (mg) Intergranular Emtricitabine 200
Tenofovir alafenamide hemifumarate 28 Microcrystalline cellulose
115 Croscarmellose sodium 30.2 Magnesium stearate 1.9 Extragranular
Magnesium stearate 1.9 Total layer weight 377
[0203] In one embodiment, the second layer of the multilayer tablet
includes:
TABLE-US-00030 Ingredient Mass (mg) Emtricitabine 200 Tenofovir
alafenamide hemifumarate 28 Microcrystalline cellulose 113.2
Croscarmellose sodium 30.2 Magnesium stearate 5.7
[0204] In one embodiment, the second layer of the multilayer tablet
includes:
TABLE-US-00031 Ingredient Mass (mg) Emtricitabine 200 Tenofovir
alafenamide hemifumarate 28 Microcrystalline cellulose 115
Croscarmellose sodium 30.2 Magnesium stearate 3.8
[0205] In one embodiment, the second layer of the multilayer tablet
includes:
TABLE-US-00032 Ingredient Mass (mg) Intergranular Emtricitabine 200
Tenofovir alafenamide hemifumarate 28 Microcrystalline cellulose
113.2 Croscarmellose sodium 30.2 Magnesium stearate 2.85
Extragranular Magnesium stearate 2.85 Total layer weight 377
[0206] In one embodiment of the multilayer tablet formulations
disclosed herein, the first layer is in contact with the second
layer.
[0207] In one embodiment, the first layer is produced first,
followed be the second layer. That is, in one embodiment, the first
layer is prepared and pressed into a first layer, followed by the
second layer being prepared and being pressed with the first layer
into a multilayer tablet. In one embodiment, the second layer is
produced first, followed be the first layer. That is, in one
embodiment, the second layer is prepared and pressed into a second
layer, followed by the first layer being prepared and being pressed
with the second layer into a multilayer tablet.
[0208] As used herein, when describing the multilayer tablets
disclosed herein, the terms "first layer" and "second layer" are
not intended to indicate the method by which the tablets are
produced, in particular the order in which the layers are
obtained.
[0209] In certain embodiments, the multilayer tablet further
comprises additional layers. In certain embodiments, the additional
layer or layers are located between the first and second layers. In
certain embodiments, the additional layer or layers are located on
either side of the first and/or second layer, such that they are an
outside layer of the table and/or are disposed between the first
and/or second layer and a coating layer. In some embodiments, the
additional layer or layers encapsulate the first and second
layers.
[0210] In one embodiment, the multilayer tablet further comprises a
third layer that is between and that separates the first layer and
the second layer. In one embodiment, the third layer of the
multilayer tablet comprises lactose monohydrate, or
microcrystalline cellulose, or a mixture thereof.
[0211] In one embodiment, the multilayer tablet further comprises a
film coating. In one embodiment, the multilayer tablet further
comprises about 14 mg to about 28 mg of a film coating. In one
embodiment, the multilayer tablet further comprises about 19 mg to
about 23 mg of a film coating. In one embodiment, the multilayer
tablet further comprises about 21 mg of a film coating. In one
embodiment the film coating comprises polyvinyl alcohol,
polyethylene glycol, talc, titanium dioxide, and black iron oxide.
In one embodiment the film coating consists of 21.+-.7 mg of Opadry
II Brown 85F165072. In one embodiment the film coating consists of
21.+-.7 mg of Opadry II Yellow 85F92259.
[0212] In one embodiment, the multilayer tablet further includes a
film coating. In one embodiment, the multilayer tablet further
comprises about 1.9% to about 3.9% w/w of a film coating. In one
embodiment, the multilayer tablet further comprises about 2.5% to
about 3.5% w/w of a film coating. In one embodiment, the multilayer
tablet further comprises about 3% of a film coating. In one
embodiment the film coating includes polyvinyl alcohol,
polyethylene glycol, talc, titanium dioxide, iron oxide red, and
black iron oxide. In one embodiment the film coating includes
36%-40% polyvinyl alcohol, 18%-22% polyethylene glycol, 13%-16%
talc, 20%-24% titanium dioxide, 2%-3% iron oxide red, and 0.5%47%
black iron oxide.
[0213] In one embodiment a tablet is provided comprising about
6.4-8.5% w/w of the compound of Formula II, about 25-32% w/w mg
emtricitabine, about 3.5-4.5% w/w mg tenofovir alafenamide
hemifumarate, about 46-57% w/w mg microcrystalline cellulose, about
5.9-8.5% w/w mg croscarmellose sodium, and about 1.0-2.0% w/w mg
magnesium stearate.
[0214] In one embodiment a tablet is provided comprising 52.+-.6 mg
of the compound of Formula II, 200.+-.20 mg emtricitabine, 28.+-.3
mg tenofovir alafenamide hemifumarate, 360.+-.30 mg
Microcrystalline cellulose, 50.+-.8 mg Croscarmellose sodium, and
10.5.+-.3 mg magnesium stearate and wherein the total weight of the
tablet is at least about 685 mg.
[0215] In one embodiment a tablet is provided comprising 52.+-.6 mg
of the compound of Formula II, 200.+-.10 mg emtricitabine,
28.+-.1.5 mg tenofovir alafenamide hemifumarate, 360.+-.15 mg
Microcrystalline cellulose, 50.+-.4 mg Croscarmellose sodium, and
10.5.+-.1.5 mg magnesium stearate and wherein the total weight of
the tablet is at least about 685 mg and is less than about 715
mg.
[0216] In one embodiment a tablet is provided comprising 52.+-.6 mg
of the compound of Formula II, 200.+-.20 mg emtricitabine, 28.+-.3
mg Tenofovir alafenamide hemifumarate, 360.+-.30 mg
Microcrystalline cellulose, 50.+-.8 mg Croscarmellose sodium, and
8.6.+-.3 mg magnesium stearate and wherein the total weight of the
tablet is at least about 685 mg.
[0217] In one embodiment a tablet is provided comprising 52.+-.6 mg
of the compound of Formula II, 200.+-.10 mg emtricitabine,
28.+-.1.5 mg Tenofovir alafenamide hemifumarate, 360.+-.15 mg
Microcrystalline cellulose, 50.+-.4 mg Croscarmellose sodium, and
8.6.+-.1.5 mg magnesium stearate and wherein the total weight of
the tablet is at least about 685 mg and is less than about 715
mg.
[0218] In one embodiment, the tablet has a total weight of
700.+-.75 mg, or 700.+-.25 mg, or 700.+-.10 mg, or 700 mg. In one
embodiment, the tablet is uncoated and has a total weight of about
700.+-.75 mg, or about 700.+-.25 mg, or about 700.+-.10 mg, or
about 700 mg. In one embodiment, the tablet has a total weight of
about 720.+-.75 mg, or about 720.+-.25 mg, or about 720.+-.10 mg,
or about 720 mg, or about 721 mg, or about 722 mg, or about 723 mg,
or about 724 mg, or about 725 mg, or about 726 mg, or about 727 mg,
or about 728 mg, or about 729 mg, or about 730 mg.
[0219] In one embodiment a tablet is provided comprising 80.+-.6 mg
of the compound of Formula II, 200.+-.20 mg emtricitabine, 28.+-.3
mg Tenofovir alafenamide hemifumarate, 360.+-.30 mg
Microcrystalline cellulose, 50.+-.8 mg Croscarmellose sodium, and
11.+-.3 mg magnesium stearate and wherein the total weight of the
tablet is at least about 715 mg.
[0220] In one embodiment a tablet is provided comprising 78.+-.2.3
mg of the compound of Formula II, 200.+-.10 mg emtricitabine,
28.+-.1.5 mg Tenofovir alafenamide hemifumarate, 361.+-.15 mg
Microcrystalline cellulose, 51.+-.4 mg Croscarmellose sodium, and
11.+-.1.5 mg magnesium stearate and wherein the total weight of the
tablet is at least about 715 mg and is less than about 745 mg.
[0221] In one embodiment, the tablet has a total weight of
730.+-.75 mg, or 730.+-.25 mg, or 730.+-.10 mg, or 730 mg. In one
embodiment, the tablet has a total weight of about 750.+-.75 mg, or
about 750.+-.25 mg, or about 750.+-.10 mg, or about 750 mg, or
about 751 mg, or about 752 mg, or about 753 mg, or about 754 mg, or
about 755 mg.
[0222] In one embodiment, a tablet is provided comprising:
TABLE-US-00033 Ingredient Mass (mg) The compound of Formula II 52
.+-. 6 Emtricitabine 200 .+-. 20 Tenofovir alafenamide hemifumarate
28 .+-. 3 Microcrystalline cellulose 360 .+-. 30 Croscarmellose
sodium 50 .+-. 8 Magnesium stearate 10.5 .+-. 3
[0223] In one embodiment, a tablet is provided comprising:
TABLE-US-00034 Ingredient Mass (mg) The compound of Formula II 52.5
.+-. 3 Emtricitabine 200 .+-. 10 Tenofovir alafenamide hemifumarate
28.1 .+-. 1.5 Microcrystalline cellulose 360 .+-. 15 Croscarmellose
sodium 50 .+-. 4 Magnesium stearate 10.5 .+-. 1.5
[0224] In one embodiment, a tablet is provided including:
TABLE-US-00035 Ingredient Mass (mg) The compound of Formula I, or a
50 .+-. 5 pharmaceutically acceptable salt thereof Emtricitabine
200 .+-. 20 Tenofovir alafenamide, or a pharmaceutically 25 .+-. 3
acceptable salt thereof Microcrystalline cellulose 360 .+-. 30
Croscarmellose sodium 50 .+-. 8 Magnesium stearate 8.6 .+-. 3
[0225] In one embodiment, a tablet is provided including:
TABLE-US-00036 Ingredient Mass (mg) The compound of Formula I, or a
50 .+-. 2.5 pharmaceutically acceptable salt thereof Emtricitabine
200 .+-. 10 Tenofovir alafenamide, or a pharmaceutically 25 .+-.
1.5 acceptable salt thereof Microcrystalline cellulose 360 .+-. 15
Croscarmellose sodium 50 .+-. 4 Magnesium stearate 8.6 .+-. 1.5
[0226] In one embodiment, a tablet is provided including:
TABLE-US-00037 Ingredient Mass (mg) The compound of Formula I, or a
52 .+-. 6 pharmaceutically acceptable salt thereof Emtricitabine
200 .+-. 20 Tenofovir alafenamide hemifumarate 28 .+-. 3
Microcrystalline cellulose 360 .+-. 30 Croscarmellose sodium 50
.+-. 8 Magnesium stearate 8.6 .+-. 3
[0227] In one embodiment, a tablet is provided including:
TABLE-US-00038 Ingredient Mass (mg) The compound of Formula II 52
.+-. 6 Emtricitabine 200 .+-. 20 Tenofovir alafenamide hemifumarate
28 .+-. 3 Microcrystalline cellulose 360 .+-. 30 Croscarmellose
sodium 50 .+-. 8 Magnesium stearate 8.6 .+-. 3
[0228] In one embodiment, a tablet is provided including:
TABLE-US-00039 Ingredient Mass (mg) The compound of Formula II 52.5
.+-. 3 Emtricitabine 200 .+-. 10 Tenofovir alafenamide hemifumarate
28.1 .+-. 1.5 Microcrystalline cellulose 360 .+-. 15 Croscarmellose
sodium 50 .+-. 4 Magnesium stearate 8.6 .+-. 1.5
[0229] In one embodiment, a tablet is provided comprising a first
layer consisting of:
TABLE-US-00040 Ingredient Mass (mg) The compound of Formula II 50
.+-. 6 Microcrystalline cellulose 250 .+-. 20 Croscarmellose sodium
20 .+-. 5 Magnesium stearate 5 .+-. 1.5
and a second layer consisting of:
TABLE-US-00041 Ingredient Mass (mg) Emtricitabine 200 .+-. 20
Tenofovir alafenamide hemifumarate 28 .+-. 3 Microcrystalline
cellulose 113 .+-. 9 Croscarmellose sodium 30 .+-. 3 Magnesium
stearate 5.6 .+-. 1.1
[0230] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00042 Ingredient Mass (mg) The compound of Formula I, or a
50 .+-. 6 pharmaceutically acceptable salt thereof Microcrystalline
cellulose 250 .+-. 20 Croscarmellose sodium 20 .+-. 5 Magnesium
stearate 5 .+-. 1.5
and a second layer including:
TABLE-US-00043 Ingredient Mass (mg) Emtricitabine 200 .+-. 20
Tenofovir alafenamide, or a 25 .+-. 3 pharmaceutically acceptable
salt thereof Microcrystalline cellulose 113 .+-. 9 Croscarmellose
sodium 30 .+-. 3 Magnesium stearate 4 .+-. 1.1
[0231] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00044 Ingredient Mass (mg) The compound of Formula I, or a
50 .+-. 6 pharmaceutically acceptable salt thereof Microcrystalline
cellulose 250 .+-. 20 Croscarmellose sodium 20 .+-. 5 Magnesium
stearate 5 .+-. 1.5
and a second layer including:
TABLE-US-00045 Ingredient Mass (mg) Emtricitabine 200 .+-. 20
Tenofovir alafenamide hemifumarate 28 .+-. 3 Microcrystalline
cellulose 113 .+-. 9 Croscarmellose sodium 30 .+-. 3 Magnesium
stearate 4 .+-. 1.1
[0232] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00046 Ingredient Mass (mg) The compound of Formula II 50
.+-. 6 Microcrystalline cellulose 250 .+-. 20 Croscarmellose sodium
20 .+-. 5 Magnesium stearate 5 .+-. 1.5
and a second layer including:
TABLE-US-00047 Ingredient Mass (mg) Emtricitabine 200 .+-. 20
Tenofovir alafenamide hemifumarate 28 .+-. 3 Microcrystalline
cellulose 113 .+-. 9 Croscarmellose sodium 30 .+-. 3 Magnesium
stearate 4 .+-. 1.1
[0233] In one embodiment, a tablet is provided comprising a first
layer consisting of:
TABLE-US-00048 Ingredient Mass (mg) The compound of Formula II 52
.+-. 2.8 Microcrystalline cellulose 246 .+-. 5 Croscarmellose
sodium 19 .+-. 1.75 Magnesium stearate 5 .+-. 0.5
and a second layer consisting of:
TABLE-US-00049 Ingredient Mass (mg) Emtricitabine 200 .+-. 10
Tenofovir alafenamide hemifumarate 28 .+-. 1.4 Microcrystalline
cellulose 113 .+-. 4 Croscarmellose sodium 30 .+-. 1.4 Magnesium
stearate 5.6 .+-. 0.5
[0234] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00050 Ingredient Mass (mg) The compound of Formula I, or a
50 .+-. 3 pharmaceutically acceptable salt therof Microcrystalline
cellulose 246 .+-. 5 Croscarmellose sodium 19 .+-. 1.75 Magnesium
stearate 5 .+-. 0.5
and a second layer including:
TABLE-US-00051 Ingredient Mass (mg) Emtricitabine 200 .+-. 10
Tenofovir alafenamide, or a 25 .+-. 3 pharmacetuically acceptable
salt thereof Microcrystalline cellulose 113 .+-. 4 Croscarmellose
sodium 30 .+-. 1.4 Magnesium stearate 4 .+-. 0.5
[0235] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00052 Ingredient Mass (mg) The compound of Formula II 52
.+-. 2.8 Microcrystalline cellulose 246 .+-. 5 Croscarmellose
sodium 19 .+-. 1.75 Magnesium stearate 5 .+-. 0.5
and a second layer including:
TABLE-US-00053 Ingredient Mass (mg) Emtricitabine 200 .+-. 10
Tenofovir alafenamide hemifumarate 28 .+-. 1.4 Microcrystalline
cellulose 113 .+-. 4 Croscarmellose sodium 30 .+-. 1.4 Magnesium
stearate 4 .+-. 0.5
[0236] In one embodiment, a tablet is provided comprising:
TABLE-US-00054 Ingredient Mass (mg) The compound of Formula II 80
.+-. 6 Emtricitabine 200 .+-. 20 Tenofovir alafenamide hemifumarate
28 .+-. 3 Microcrystalline cellulose 360 .+-. 30 Croscarmellose
sodium 50 .+-. 8 Magnesium stearate 11 .+-. 3
[0237] In one embodiment, a tablet is provided comprising:
TABLE-US-00055 Ingredient Mass (mg) The compound of Formula II 78.6
.+-. 2.3 Emtricitabine 200 .+-. 10 Tenofovir alafenamide
hemifumarate 28.1 .+-. 1.5 Microcrystalline cellulose 361 .+-. 15
Croscarmellose sodium 51 .+-. 4 Magnesium stearate 11 .+-. 1.5
[0238] In one embodiment, a tablet is provided comprising a first
layer consisting of:
TABLE-US-00056 Ingredient Mass (mg) The compound of Formula II 80
.+-. 6 Microcrystalline cellulose 250 .+-. 20 Croscarmellose sodium
20 .+-. 5 Magnesium stearate 5 .+-. 1.5
and a second layer consisting of:
TABLE-US-00057 Ingredient Mass (mg) Emtricitabine 200 .+-. 20
Tenofovir alafenamide hemifumarate 28 .+-. 3 Microcrystalline
cellulose 113 .+-. 9 Croscarmellose sodium 30 .+-. 3 Magnesium
stearate 5.6 .+-. 1.1
[0239] In one embodiment, a tablet is provided comprising a first
layer consisting of:
TABLE-US-00058 Ingredient Mass (mg) The compound of Formula II 78
.+-. 2.8 Microcrystalline cellulose 247 .+-. 5 Croscarmellose
sodium 21 .+-. 1.75 Magnesium stearate 5 .+-. 0.5
and a second layer consisting of:
TABLE-US-00059 Ingredient Mass (mg) Emtricitabine 200 .+-. 10
Tenofovir alafenamide hemifumarate 28 .+-. 1.4 Microcrystalline
cellulose 113 .+-. 4 Croscarmellose sodium 30 .+-. 1.4 Magnesium
stearate 5.6 .+-. 0.5
[0240] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00060 % w/w (in tablet) The compound of Formula I, 5-10 or
a pharmaceutically acceptable salt thereof Microcrystalline
cellulose 26-44 Croscarmellose sodium 2-4 Magnesium stearate
0.5-0.9
and a second layer including:
TABLE-US-00061 % w/w (in tablet) Emtricitabine 21-36 Tenofovir
alafenamide, or a pharmaceutically 3-5 acceptable salt thereof
Microcrystalline cellulose 12-20 Croscarmellose sodium 3-6
Magnesium stearate 0.3-0.7
and optionally a film coating.
[0241] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00062 % w/w (in tablet) The compound of Formula II 5-10
Microcrystalline cellulose 26-44 Croscarmellose sodium 2-4
Magnesium stearate 0.5-0.9
and a second layer including:
TABLE-US-00063 % w/w (in tablet) Emtricitabine 21-36 Tenofovir
alafenamide hemifumarate 3-5 Microcrystalline cellulose 12-20
Croscarmellose sodium 3-6 Magnesium stearate 0.3-0.7
[0242] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00064 % w/w (in tablet) The compound of Formula I, 6-9 or
a pharmaceutically acceptable salt thereof Microcrystalline
cellulose 30-40 Croscarmellose sodium 2.4-3.2 Magnesium stearate
0.6-0.8
and a second layer including:
TABLE-US-00065 % w/w (in tablet) Emtricitabine 24-33 Tenofovir
alafenamide, or a pharmaceutically 3.4-4.6 acceptable salt thereof
Microcrystalline cellulose 14-19 Croscarmellose sodium 3.6-4.9
Magnesium stearate 0.6-0.8
and optionally a film coating.
[0243] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00066 % w/w (in tablet) The compound of Formula II 6-9
Microcrystalline cellulose 30-40 Croscarmellose sodium 2.4-3.2
Magnesium stearate 0.6-0.8
and a second layer including:
TABLE-US-00067 % w/w (in tablet) Emtricitabine 24-33 Tenofovir
alafenamide hemifumarate 3.4-4.6 Microcrystalline cellulose 14-19
Croscarmellose sodium 3.6-4.9 Magnesium stearate 0.6-0.8
[0244] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00068 % w/w (in tablet) The compound of Formula II 7-8
Microcrystalline cellulose 32-37 Croscarmellose sodium 2.7-2.9
Magnesium stearate 0.6-0.8
and a second layer including:
TABLE-US-00069 % w/w (in tablet) Emtricitabine 26-30 Tenofovir
alafenamide hemifumarate 3.7-4.6 Microcrystalline cellulose 15-17
Croscarmellose sodium 4.0-4.5 Magnesium stearate 0.5-0.6
and optionally a film coating.
[0245] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00070 % w/w (in tablet) The compound of Formula II 7-8
Microcrystalline cellulose 33-36 Croscarmellose sodium 2.7-2.8
Magnesium stearate 0.7-0.8
and a second layer including:
TABLE-US-00071 % w/w (in tablet) Emtricitabine 27-29 Tenofovir
alafenamide hemifumarate 3.8-4.2 Microcrystalline cellulose 16-17
Croscarmellose sodium 4.1-4.4 Magnesium stearate 0.5-0.8
[0246] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00072 % w/w (in tablet) The compound of Formula II 7.5
Microcrystalline cellulose 35.2 Croscarmellose sodium 2.8 Magnesium
stearate 0.7
and a second layer including:
TABLE-US-00073 % w/w (in tablet) Emtricitabine 28.6 Tenofovir
alafenamide hemifumarate 4.0 Microcrystalline cellulose 16.4
Croscarmellose sodium 4.3 Magnesium stearate 0.5
and optionally a film coating.
[0247] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00074 % w/w (in tablet) The compound of Formula II 7.5
Microcrystalline cellulose 35.2 Croscarmellose sodium 2.8 Magnesium
stearate 0.7
and a second layer including:
TABLE-US-00075 % w/w (in tablet) Emtricitabine 28.6 Tenofovir
alafenamide hemifumarate 4.0 Microcrystalline cellulose 16.2
Croscarmellose sodium 4.3 Magnesium stearate 0.8
[0248] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00076 % w/w (in layer) Intergranular The compound of
Formula I, 11-19 or a pharmaceutically accpetable salt thereof
Microcrystalline cellulose 51-86 Croscarmellose sodium 4-7
Magnesium stearate 0.5-0.9 Extragranular Microcrystalline cellulose
7-12 Magnesium stearate 0.5-0.9
and a second layer including:
TABLE-US-00077 % w/w (in layer) Intergranular Emtricitabine 39-67
Tenofovir alafenamide, or a pharmaceutically 5-10 acceptable salt
thereof Microcrystalline cellulose 22-38 Croscarmellose sodium 6-10
Magnesium stearate 0.3-0.7 Intergranular Magnesium stearate
0.3-0.7
[0249] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00078 % w/w (in layer) Intergranular The compound of
Formula II 11-19 Microcrystalline cellulose 51-86 Croscarmellose
sodium 4-7 Magnesium stearate 0.5-0.9 Extragranular
Microcrystalline cellulose 7-12 Magnesium stearate 0.5-0.9
and a second layer including:
TABLE-US-00079 % w/w (in layer) Intergranular Emtricitabine 39-67
Tenofovir alafenamide hemifumarate 5-10 Microcrystalline cellulose
22-38 Croscarmellose sodium 6-10 Magnesium stearate 0.3-0.7
Intergranular Magnesium stearate 0.3-0.7
[0250] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00080 % w/w (in layer) Intergranular The compound of
Formula I, or a 13-17 pharmaceutically acceptable salt thereof
Microcrystalline cellulose 58-79 Croscarmellose sodium 4.6-6.3
Magnesium stearate 0.6-0.8 Extragranular Microcrystalline cellulose
5-11 Magnesium stearate 0.6-0.8
and a second layer including:
TABLE-US-00081 % w/w (in layer) Intergranular Emtricitabine 45-61
Tenofovir alafenamide, or a pharmaceutically 6-9 acceptable salt
thereof Microcrystalline cellulose 25-35 Croscarmellose sodium
6.5-9.2 Magnesium stearate 0.4-0.5 Intergranular Magnesium stearate
0.4-0.5
[0251] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00082 % w/w (in layer) Intergranular The compound of
Formula II 13-17 Microcrystalline cellulose 58-79 Croscarmellose
sodium 4.6-6.3 Magnesium stearate 0.6-0.8 Extragranular
Microcrystalline cellulose 5-11 Magnesium stearate 0.6-0.8
and a second layer including:
TABLE-US-00083 % w/w (in layer) Intergranular Emtricitabine 45-61
Tenofovir alafenamide hemifumarate 6-9 Microcrystalline cellulose
25-35 Croscarmellose sodium 6.5-9.2 Magnesium stearate 0.4-0.5
Intergranular Magnesium stearate 0.4-0.5
[0252] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00084 % w/w (in layer) Intergranular The compound of
Formula I, 14-16 or a pharmaceutically acceptable salt thereof
Microcrystalline cellulose 66-73 Croscarmellose sodium 5.2-5.8
Magnesium stearate 0.65-0.75 Extragranular Microcrystalline
cellulose 8-10 Magnesium stearate 0.65-0.75
and a second layer including:
TABLE-US-00085 % w/w (in layer) Intergranular Emtricitabine 50-56
Tenofovir alafenamide, or a pharmaceutically 7-8 acceptable salt
thereof Microcrystalline cellulose 28-32 Croscarmellose sodium
7.5-8.5 Magnesium stearate 0.45-0.55 Intergranular Magnesium
stearate 0.45-0.55
[0253] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00086 % w/w (in layer) Intergranular The compound of
Formula II 14-16 Microcrystalline cellulose 66-73 Croscarmellose
sodium 5.2-5.8 Magnesium stearate 0.65-0.75 Extragranular
Microcrystalline cellulose 8-10 Magnesium stearate 0.65-0.75
and a second layer including:
TABLE-US-00087 % w/w (in layer) Intergranular Emtricitabine 50-56
Tenofovir alafenamide hemifumarate 7-8 Microcrystalline cellulose
28-32 Croscarmellose sodium 7.5-8.5 Magnesium stearate 0.45-0.55
Intergranular Magnesium stearate 0.45-0.55
[0254] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00088 % w/w (in layer) Intergranular The compound of
Formula II 15 Microcrystalline cellulose 69 Croscarmellose sodium
5.5 Magnesium stearate 0.7 Extragranular Microcrystalline cellulose
9 Magnesium stearate 0.7
and a second layer including:
TABLE-US-00089 % w/w (in layer) Intergranular Emtricitabine 53
Tenofovir alafenamide hemifumarate 7.5 Microcrystalline cellulose
30 Croscarmellose sodium 8 Magnesium stearate 0.5 Intergranular
Magnesium stearate 0.5
[0255] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00090 % w/w (in layer) Intergranular The compound of
Formula II 15 Microcrystalline cellulose 69 Croscarmellose sodium
5.5 Magnesium stearate 0.7 Extragranular Microcrystalline cellulose
9 Magnesium stearate 0.7
and a second layer including:
TABLE-US-00091 % w/w (in layer) Intergranular Emtricitabine 53
Tenofovir alafenamide hemifumarate 7.5 Microcrystalline cellulose
30 Croscarmellose sodium 8 Magnesium stearate 0.7 Intergranular
Magnesium stearate 0.7
[0256] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00092 Mass (mg) % w/w (in layer) Intragranular The
compound of Formula II 52.5 16.24 Microcrystalline cellulose
149.9-246.3 46.41-76.26 Croscarmellose sodium 19.4 8.00 Magnesium
stearate 1.98-2.45 0.6-1.0 Extragranular Microcrystalline cellulose
0-97.0 0-30 Magnesium stearate 1.98-2.45 0.6-1.0
and a second layer including:
TABLE-US-00093 Mass (mg) % w/w (in layer) Intergranular
Emtricitabine 200.00 53.05 Tenofovir alafenamide hemifumarate 28.1
7.45 Microcrystalline cellulose 113.2 30 Croscarmellose sodium 30.2
8.00 Magnesium stearate 1.93-2.85 0.50-0.75 Extragranular Magnesium
stearate 1.93-2.85 0.50-0.75
[0257] In one embodiment, a tablet is provided comprising a first
layer consisting of:
TABLE-US-00094 Mass (mg) % w/w (in layer) Intergranular The
compound of Formula II 52.5 16.24 Microcrystalline cellulose
149.9-246.3 46.41-76.26 Croscarmellose sodium 19.4 8.00 Magnesium
stearate 1.98-2.45 0.6-1.0 Extragranular Microcrystalline cellulose
0-97.0 0-30 Magnesium stearate 1.98-2.45 0.6-1.0
and a second layer consisting of:
TABLE-US-00095 Mass (mg) % w/w (in layer) Intergranular
Emtricitabine 200.00 53.05 Tenofovir alafenamide hemifumarate 28.1
7.45 Microcrystalline cellulose 113.2 30 Croscarmellose sodium 30.2
8.00 Magnesium stearate 1.93-2.85 0.50-0.75 Extragranular Magnesium
stearate 1.93-2.85 0.50-0.75
[0258] In one embodiment, a tablet is provided comprising a first
layer consisting of:
TABLE-US-00096 Mass (mg) % w/w (in layer) Intergranular The
compound of Formula II 78.7 22.3 Microcrystalline cellulose 212.5
60.2 Croscarmellose sodium 21.2 6.00 Magnesium stearate 2.65 0.75
Extragranular Microcrystalline cellulose 35.30 10.0 Magnesium
stearate 2.65 0.75
and a second layer consisting of:
TABLE-US-00097 Mass (mg) % w/w (in layer) Intergranular
Emtricitabine 200.00 53.05 Tenofovir alafenamide hemifumarate 28.0
7.4 Microcrystalline cellulose 113.2 30 Croscarmellose sodium 30.2
8.00 Magnesium stearate 2.83 0.75 Extragranular Magnesium stearate
2.83 0.75
[0259] In one embodiment, a tablet is provided comprising a first
layer consisting of:
TABLE-US-00098 Mass (mg) % w/w (in layer) Intergranular The
compound of Formula II 52.5 16.25 Microcrystalline cellulose
0-246.3 0-76.25 Croscarmellose sodium 19.4 8.00 Magnesium stearate
1.98-2.45 0.6-1.0 Extragranular Microcrystalline cellulose 0-97.0
0-30 Magnesium stearate 2.45 0.6-1.0
and a second layer consisting of:
TABLE-US-00099 Mass (mg) % w/w (in layer) Intergranular
Emtricitabine 200.00 53.05 Tenofovir alafenamide hemifumarate 28.1
7.45 Microcrystalline cellulose 113.2 30 Croscarmellose sodium 30.2
8.00 Magnesium stearate 2.85 0.75 Extragranular Magnesium stearate
2.85 0.75
and a film coating consisting of 21 mg of Opadry II Brown 85F165072
(a combination of polyvinyl alcohol, polyethylene glycol (PEG),
talc, titanium dioxide, iron oxide red, and iron oxide black).
[0260] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00100 Mass (mg) % w/w (in layer) Intergranular The
compound of Formula II 52.5 13-21 Microcrystalline cellulose 0-246
0-59 Croscarmellose sodium 19 5-25 Magnesium stearate 2.0-2.5
0.5-3.2 Extragranular Microcrystalline cellulose 0-97 0-30
Magnesium stearate 2.0-2.5 0.5-3.2
and a second layer including:
TABLE-US-00101 Mass (mg) % w/w (in layer) Intergranular
Emtricitabine 200 35 Tenofovir alafenamide hemifumarate 28 4.9
Microcrystalline cellulose 113 20 Croscarmellose sodium 30 5.2
Magnesium stearate 2.9 0.5 Extragranular Magnesium stearate 2.9
0.5
and a film coating consisting of 21 mg of Opadry II Brown 85F165072
(a combination of polyvinyl alcohol, polyethylene glycol (PEG),
talc, titanium dioxide, iron oxide red, and iron oxide black).
[0261] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00102 Mass (mg) % w/w (in tablet) The compound of Formula
II 47-58 6.75-8.25 Microcrystalline cellulose 222-271 32-59
Croscarmellose sodium 17-21 2.5-3.1 Magnesium stearate 4.4-5.4
0.6-0.8
and a second layer including:
TABLE-US-00103 Mass (mg) % w/w (in tablet) Emtricitabine 180-220
26-31 Tenofovir alafenamide hemifumarate 25-31 3.6-4.4
Microcrystalline cellulose 104-127 15-18 Croscarmellose sodium
27-33 2.6-4.7 Magnesium stearate 3.4-6.0 0.4-1.0
and optionally a film coating (e.g., Opadry II Brown 85F165072 (a
combination of polyvinyl alcohol, polyethylene glycol (PEG), talc,
titanium dioxide, iron oxide red, and iron oxide black).
[0262] In one embodiment, a tablet is provided comprising a first
layer including:
TABLE-US-00104 Mass (mg) % w/w (in tablet) The compound of Formula
II 52.5 7.5 Microcrystalline cellulose 246 35 Croscarmellose sodium
19 2.8 Magnesium stearate 5 0.7
and a second layer including:
TABLE-US-00105 Mass (mg) % w/w (in tablet) Emtricitabine 200 29
Tenofovir alafenamide hemifumarate 28 4 Microcrystalline cellulose
115 16 Croscarmellose sodium 30 4.3 Magnesium stearate 4 0.5
and optionally a film coating (e.g., Opadry II Brown 85F165072 (a
combination of polyvinyl alcohol, polyethylene glycol (PEG), talc,
titanium dioxide, iron oxide red, and iron oxide black).
[0263] In one embodiment, a tablet is provided comprising a first
layer consisting of:
TABLE-US-00106 Mass (mg) % w/w (in layer) Intergranular The
compound of Formula II 78.6 22.3 Microcrystalline cellulose 212.5
60.2 Croscarmellose sodium 21.2 6.00 Magnesium stearate 2.65 0.75
Extragranular Microcrystalline cellulose 35.3 10.0 Magnesium
stearate 2.65 0.75
and a second layer consisting of:
TABLE-US-00107 Mass (mg) % w/w (in layer) Intergranular
Emtricitabine 200.00 53.05 Tenofovir alafenamide hemifumarate 28.1
7.45 Microcrystalline cellulose 113.1 30 Croscarmellose sodium 30.2
8.00 Magnesium stearate 2.85 0.75 (0.5-0.75) Extragranular
Magnesium stearate 2.83 0.75 (0.5-7.5)
and a film coating consisting of 21.9 mg of Opadry II Yellow
85F92259 (a combination of polyvinyl alcohol, polyethylene glycol
(PEG), talc, titanium dioxide and iron yellow).
[0264] In one embodiment, a composition is provided including about
75 mg of a compound of Formula I, or a pharmaceutically acceptable
salt thereof (e.g., a compound of Formula II), about 25 mg
tenofovir alafenamide, or a pharmaceutically acceptable salt
thereof, and about 200 mg emtricitabine, or a pharmaceutically
acceptable salt thereof, wherein the mean AUC.sub.last of each
component following a single dose administered to a human is from
about 81700 h-ng/mL to about 140000 h-ng/mL of the compound of
Formula I, from about 7500 h-ng/mL to about 15000 h-ng/mL of
emtricitabine, and from about 165 h-ng/mL to about 400 h-ng/mL of
tenofovir alafenamide. In certain embodiments, the composition is
administered to the human in a fasted state. In certain
embodiments, the composition is a tablet. In certain embodiments,
the tablet is a bilayer tablet. In certain embodiments, the tablet
is a bilayer tablet, with the Compound of Formula I in one layer
and emtricitabine and tenofovir alafenamide in the other layer.
[0265] In one embodiment, a composition is provided including a
compound of 50 mg Formula I, or a pharmaceutically acceptable salt
thereof (e.g., a compound of Formula II), 25 mg tenofovir
alafenamide, or a pharmaceutically acceptable salt thereof, and 200
mg emtricitabine, or a pharmaceutically acceptable salt thereof,
wherein the mean AUC.sub.last of each component following a single
dose is from about 87,000 h-ng/mL to about 131,000 h-ng/mL of the
compound of Formula I, from about 8500 h-ng/mL to about 12,800
h-ng/mL of emtricitabine, and from about 186 h-ng/mL to about 227
h-ng/mL of tenofovir alafenamide. In certain embodiments, the
composition is administered to the human in a fasted state. In
certain embodiments, the composition is a tablet. In certain
embodiments, the tablet is a bilayer tablet. In certain
embodiments, the tablet is a bilayer tablet, with the Compound of
Formula I in one layer and emtricitabine and tenofovir alafenamide
in the other layer. In certain embodiments, the subject is fasted.
In other embodiments, the subject is fed.
[0266] In one embodiment, a composition is provided including a
compound of Formula I, or a pharmaceutically acceptable salt
thereof (e.g., a compound of Formula II), tenofovir alafenamide, or
a pharmaceutically acceptable salt thereof, and emtricitabine, or a
pharmaceutically acceptable salt thereof, wherein the mean
AUC.sub.inf of each component following a single dose administered
to a human is from about 84450 h-ng/mL to about 141000 h-ng/mL of
the compound of Formula I, from about 8100 h-ng/mL to about 136000
h-ng/mL of emtricitabine, and from about 200 h-ng/mL to about 500
h-ng/mL of tenofovir alafenamide. In certain embodiments, the
composition is administered to the human in a fasted state. In
certain embodiments, the composition is a tablet. In certain
embodiments, the tablet is a bilayer tablet. In certain
embodiments, the tablet is a bilayer tablet, with the Compound of
Formula I in one layer and emtricitabine and tenofovir alafenamide
in the other layer. In certain embodiments, the subject is fasted.
In other embodiments, the subject is fed.
[0267] In one embodiment, a composition is provided including a
compound of Formula I (e.g., a compound of Formula II), tenofovir
alafenamide, and emtricitabine, wherein the mean C.sub.max of each
component following a single dose is from about 90,000 h-ng/mL to
about 135,000 h-ng/mL of the compound of Formula I, from about
8,700 h-ng/mL to about 13,000 h-ng/mL of emtricitabine, and from
about 200 h-ng/mL to about 300 h-ng/mL of tenofovir alafenamide. In
certain embodiments, the composition is administered to the human
in a fasted state. In certain embodiments, the composition is a
tablet. In certain embodiments, the tablet is a bilayer tablet. In
certain embodiments, the tablet is a bilayer tablet, with the
Compound of Formula I in one layer and emtricitabine and tenofovir
alafenamide in the other layer. In certain embodiments, the subject
is fasted. In other embodiments, the subject is fed.
[0268] In one embodiment, a composition is provided including a
compound of Formula I, or a pharmaceutically acceptable salt
thereof (e.g., a compound of Formula II), tenofovir alafenamide, or
a pharmaceutically acceptable salt thereof, and emtricitabine, or a
pharmaceutically acceptable salt thereof, wherein the mean
C.sub.max of each component following a single dose administered to
a human is from about 4200 ng/mL to about 8000 mg/mL of the
compound of Formula I, from about 1770 ng/mL to about 2800 ng/mL of
emtricitabine, and from about 185 ng/mL to about 315 ng/mL of
tenofovir alafenamide. In certain embodiments, the composition is
administered to the human in a fasted state. In certain
embodiments, the composition is a tablet. In certain embodiments,
the tablet is a bilayer tablet. In certain embodiments, the tablet
is a bilayer tablet, with the Compound of Formula I in one layer
and emtricitabine and tenofovir alafenamide in the other layer. In
certain embodiments, the subject is fasted. In other embodiments,
the subject is fed.
[0269] In one embodiment, a composition is provided including a
compound of Formula I, or a pharmaceutically acceptable salt
thereof (e.g., a compound of Formula II), tenofovir alafenamide, or
a pharmaceutically acceptable salt thereof, and emtricitabine, or a
pharmaceutically acceptable salt thereof, wherein the mean
C.sub.max of each component following a single dose is from about
4700 ng/mL to about 5300 ng/mL of the compound of Formula I, from
about 2000 ng/mL to about 2600 ng/mL of emtricitabine, and from
about 200 ng/mL to about 300 ng/mL of tenofovir alafenamide. In
certain embodiments, the composition is administered to the human
in a fasted state. In certain embodiments, the composition is a
tablet. In certain embodiments, the tablet is a bilayer tablet. In
certain embodiments, the tablet is a bilayer tablet, with the
Compound of Formula I in one layer and emtricitabine and tenofovir
alafenamide in the other layer. In certain embodiments, the subject
is fasted. In other embodiments, the subject is fed.
[0270] In one embodiment, a composition is provided including a
compound of Formula I, or a pharmaceutically acceptable salt
thereof (e.g., a compound of Formula II), tenofovir alafenamide, or
a pharmaceutically acceptable salt thereof, and emtricitabine, or a
pharmaceutically acceptable salt thereof, wherein the mean
AUC.sub.last, AUC.sub.inf, and/or C.sub.max of each component
following a single dose administered to a human in the fed state is
80-125%, 80-120%, 85-115%, 90-110%, or 95-105% of the mean
AUC.sub.last, AUC.sub.inf, and/or C.sub.max of each component
following a single dose administered to a human in the fasted
state. In certain embodiments, the composition is a tablet. In
certain embodiments, the tablet is a bilayer tablet. In certain
embodiments, the tablet is a bilayer tablet, with the Compound of
Formula I in one layer and emtricitabine and tenofovir alafenamide
in the other layer. In certain embodiments, the subject is fasted.
In other embodiments, the subject is fed.
[0271] In certain embodiments, the pharmacokinetic profile of the
compositions described herein is within acceptable ranges,
regardless of whether the subject has eaten prior to taking the
medication. Accordingly, in certain embodiments, the compositions
described herein can be taken without regard to food intake by the
subject. In certain embodiments, food intake is a low fat, moderate
fat, or high fat meal.
[0272] In one embodiment, a composition comprising 50 mg Compound
of Formula I, 25 mg tenofovir alafenamide, and 200 mg emtricitabine
is provided, wherein the mean AUC.sub.last of a single dose
following administration to fed patients is within about 100% to
about 160% of the mean AUC.sub.last of a single dose following
administration to fasted patients. In another embodiment, a
composition comprising 50 mg Compound of Formula I, 25 mg tenofovir
alafenamide, and 200 mg emtricitabine is provided, wherein the mean
AUC.sub.last of a single dose following administration to fed
patients is within about 100% to about 145% of the mean
AUC.sub.last of a single dose following administration to fasted
patients. In a further embodiment, a composition comprising 50 mg
Compound of Formula I, 25 mg tenofovir alafenamide, and 200 mg
emtricitabine is provided, wherein the mean AUC.sub.last of a
single dose following administration to fed patients is within
about 100% to about 135% of the mean AUC.sub.last of a single dose
following administration to fasted patients. In another embodiment,
a composition comprising 50 mg Compound of Formula I, 25 mg
tenofovir alafenamide, and 200 mg emtricitabine is provided,
wherein the mean AUC.sub.last of a single dose following
administration to fed patients is within about 100% to about 125%
of the mean AUC.sub.last of a single dose following administration
to fasted patients.
[0273] In certain embodiments, a composition comprising 50 mg
Compound of Formula I, 25 mg tenofovir alafenamide, and 200 mg
emtricitabine is provided, wherein the mean AUC.sub.last of a
single dose following administration to fed patients is within 60%
of the mean AUC.sub.last of a single dose following administration
to fasted patients. In another embodiment, a composition comprising
50 mg Compound of Formula I, 25 mg tenofovir alafenamide, and 200
mg emtricitabine is provided, wherein the mean AUC.sub.last of a
single dose following administration to fed patients is within 45%
of the mean AUC.sub.last of a single dose following administration
to fasted patients. In a further embodiment, a composition
comprising 50 mg Compound of Formula I, 25 mg tenofovir
alafenamide, and 200 mg emtricitabine is provided, wherein the mean
AUC.sub.last of a single dose following administration to fed
patients is within 35% of the mean AUC.sub.last of a single dose
following administration to fasted patients. In another embodiments
a composition comprising 50 mg Compound of Formula I, 25 mg
tenofovir alafenamide, and 200 mg emtricitabine is provided,
wherein the mean AUC.sub.last of a single dose following
administration to fed patients is within 25% of the mean
AUC.sub.last of a single dose following administration to fasted
patients.
[0274] In one embodiment, a composition comprising 50 mg Compound
of Formula I, 25 mg tenofovir alafenamide, and 200 mg emtricitabine
is provided, wherein the mean AUC.sub.inf of a single dose
following administration to fed patients is within about 100% to
about 160% of the mean AUC.sub.inf of a single dose following
administration to fasted patients. In another embodiment, a
composition comprising 50 mg Compound of Formula I, 25 mg tenofovir
alafenamide, and 200 mg emtricitabine is provided, wherein the mean
AUC.sub.inf of a single dose following administration to fed
patients is within about 100% to about 150% of the mean AUC.sub.inf
of a single dose following administration to fasted patients. In a
further embodiment, a composition comprising 50 mg Compound of
Formula I, 25 mg tenofovir alafenamide, and 200 mg emtricitabine is
provided, wherein the mean AUC.sub.inf of a single dose following
administration to fed patients is within about 100% to about 135%
of the mean AUC.sub.inf of a single dose following administration
to fasted patients. In another embodiment, a composition comprising
50 mg Compound of Formula I, 25 mg tenofovir alafenamide, and 200
mg emtricitabine is provided, wherein the mean AUC.sub.inf of a
single dose following administration to fed patients is within
about 100% to about 125% of the mean AUC.sub.inf of a single dose
following administration to fasted patients.
[0275] In certain embodiments, a composition comprising 50 mg
Compound of Formula I, 25 mg tenofovir alafenamide, and 200 mg
emtricitabine is provided, wherein the mean AUC.sub.inf of a single
dose following administration to fed patients is within 60% of the
mean AUC.sub.inf of a single dose following administration to
fasted patients. In another embodiment, a composition comprising 50
mg Compound of Formula I, 25 mg tenofovir alafenamide, and 200 mg
emtricitabine is provided, wherein the mean AUC.sub.inf of a single
dose following administration to fed patients is within 50% of the
mean AUC.sub.inf of a single dose following administration to
fasted patients. In a further embodiment, a composition comprising
50 mg Compound of Formula I, 25 mg tenofovir alafenamide, and 200
mg emtricitabine is provided, wherein the mean AUC.sub.inf of a
single dose following administration to fed patients is within 35%
of the mean AUC.sub.inf of a single dose following administration
to fasted patients. In another embodiments a composition comprising
50 mg Compound of Formula I, 25 mg tenofovir alafenamide, and 200
mg emtricitabine is provided, wherein the mean AUC.sub.inf of a
single dose following administration to fed patients is within 25%
of the mean AUC.sub.inf of a single dose following administration
to fasted patients.
[0276] In one embodiment, a composition comprising 50 mg Compound
of Formula I, 25 mg tenofovir alafenamide, and 200 mg emtricitabine
is provided, wherein the mean C.sub.max of a single dose following
administration to fed patients is within about 100% to about 160%
of the mean C.sub.max of a single dose following administration to
fasted patients. In another embodiment, a composition comprising 50
mg Compound of Formula I, 25 mg tenofovir alafenamide, and 200 mg
emtricitabine is provided, wherein the mean C.sub.max of a single
dose following administration to fed patients is within about 100%
to about 130% of the mean C.sub.max of a single dose following
administration to fasted patients. In a further embodiment, a
composition comprising 50 mg Compound of Formula I, 25 mg tenofovir
alafenamide, and 200 mg emtricitabine is provided, wherein the mean
C.sub.max of a single dose following administration to fed patients
is within about 100% to about 120% of the mean C.sub.max of a
single dose following administration to fasted patients. In another
embodiment, a composition comprising 50 mg Compound of Formula I,
25 mg tenofovir alafenamide, and 200 mg emtricitabine is provided,
wherein the mean C.sub.max of a single dose following
administration to fed patients is within about 100% to about 115%
of the mean C.sub.max of a single dose following administration to
fasted patients.
[0277] In certain embodiments, a composition comprising 50 mg
Compound of Formula I, 25 mg tenofovir alafenamide, and 200 mg
emtricitabine is provided, wherein the mean C.sub.max of a single
dose following administration to fed patients is within 60% of the
mean C.sub.max of a single dose following administration to fasted
patients. In another embodiment, a composition comprising 50 mg
Compound of Formula I, 25 mg tenofovir alafenamide, and 200 mg
emtricitabine is provided, wherein the mean C.sub.max of a single
dose following administration to fed patients is within 30% of the
mean C.sub.max of a single dose following administration to fasted
patients. In a further embodiment, a composition comprising 50 mg
Compound of Formula I, 25 mg tenofovir alafenamide, and 200 mg
emtricitabine is provided, wherein the mean C.sub.max of a single
dose following administration to fed patients is within 20% of the
mean C.sub.max of a single dose following administration to fasted
patients. In another embodiments a composition comprising 50 mg
Compound of Formula I, 25 mg tenofovir alafenamide, and 200 mg
emtricitabine is provided, wherein the mean C.sub.max of a single
dose following administration to fed patients is within 15% of the
mean C.sub.max of a single dose following administration to fasted
patients.
Manufacturing Methods
[0278] Methods for producing the compositions and dosage forms (in
particular tablets) disclosed herein are also provided. In some
embodiments, the method comprises (a) compressing the compound of
Formula I or a pharmaceutically acceptable salt thereof as a first
layer, and (b) compressing the tenofovir alafenamide or a
pharmaceutically acceptable salt thereof and emtricitabine or a
pharmaceutically acceptable salt thereof as a second layer. For
example, in some embodiments, the method comprises (a) compressing
the compound of Formula I or a pharmaceutically acceptable salt
thereof as a first layer, followed by (b) compressing the tenofovir
alafenamide or a pharmaceutically acceptable salt thereof and
emtricitabine or a pharmaceutically acceptable salt thereof as a
second layer. In other embodiments, the method comprises (a)
compressing the tenofovir alafenamide or a pharmaceutically
acceptable salt thereof and emtricitabine or a pharmaceutically
acceptable salt thereof followed by (b) compressing the compound of
Formula I or a pharmaceutically acceptable salt thereof as another
layer. In other embodiments, the method comprises (a) compressing
the compound of Formula I or a pharmaceutically acceptable salt
thereof as one layer followed by (b) compressing the tenofovir
alafenamide or a pharmaceutically acceptable salt thereof and
emtricitabine or a pharmaceutically acceptable salt thereof as
another layer. The first layer and second layer may be compressed
separately and subsequently combined. However, more typically, a
first layer is formed by compression and subsequently a second
layer is compressed onto the first layer. In certain embodiments,
the choice of layer order in the tableting of multilayer tablets
may have an impact on the properties of the tablets (e.g. the
adhesion of the layers within the tablet).
[0279] In some embodiments, a tablet is provided wherein the first
layer is obtainable by a method of (a) compressing the compound of
Formula I or a pharmaceutically acceptable salt thereof as a first
layer, and (b) compressing the tenofovir alafenamide or a
pharmaceutically acceptable salt thereof and emtricitabine or a
pharmaceutically acceptable salt thereof as a second layer. In
other embodiments, a tablet is provided wherein the second layer is
obtainable by a method of (a) compressing the compound of Formula I
or a pharmaceutically acceptable salt thereof as a first layer, and
(b) compressing the tenofovir alafenamide or a pharmaceutically
acceptable salt thereof and emtricitabine or a pharmaceutically
acceptable salt thereof as a first layer.
[0280] In certain embodiments, the methods will include a step of
coating the tablet cores after compression, e.g. with a film
coating as described above.
[0281] In general, tableting methods are 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 reference herein in its
entirety.
[0282] A tablet can be made by compression or molding, optionally
with one or more excipients. Compressed tablets may be prepared by
compressing in a suitable machine the active ingredient in a
free-flowing form such as a powder or granules, optionally mixed
with excipients.
Therapeutic Methods
[0283] The solid oral dosage forms (in particular tablets)
disclosed herein are used for treatment of HIV infection (e.g.
HIV-1 infection). In certain embodiments, the solid oral dosage
forms (in particular tablets) disclosed herein are used for
pre-exposure prophylaxis (PrEP) to reduce the risk of sexually
acquired HIV-1.
[0284] Accordingly, methods for treating a subject infected with
HIV are provided, comprising administering a solid oral dosage form
disclosed herein (in particular a tablet) to the subject.
Similarly, a solid oral dosage form (in particular a tablet) is
provided for use in such treatment methods. Also provided is the
use of the compound of Formula I or a pharmaceutically acceptable
salt thereof, tenofovir alafenamide or a pharmaceutically
acceptable salt thereof, and emtricitabine or a pharmaceutically
acceptable salt thereof, in the manufacture of an oral dosage form
disclosed herein (in particular a tablet) for treatment of HIV
infection. In some embodiments, the invention provides the use of
tenofovir alafenamide or a pharmaceutically acceptable salt
thereof, and emtricitabine or a pharmaceutically acceptable salt
thereof, in the manufacture of an oral dosage form disclosed herein
(in particular a tablet) for treatment of HIV infection.
[0285] In certain embodiments, the solid oral dosage forms (in
particular tablets) disclosed herein are used for pre-exposure
prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1.
Accordingly, methods for preventing infection in a subject at risk
of infection with HIV are provided, comprising administering a
solid oral dosage form disclosed herein (in particular a tablet) to
the subject. Similarly, a solid oral dosage form disclosed herein
(in particular a tablet) is provided for use in such treatment
methods. The invention also provides the use of the compound of
Formula I or a pharmaceutically acceptable salt thereof, tenofovir
alafenamide or a pharmaceutically acceptable salt thereof, and
emtricitabine or a pharmaceutically acceptable salt thereof, in the
manufacture of an oral dosage form disclosed herein (in particular
a tablet) for prevention of HIV infection in a subject at risk for
infection. In some embodiments, the invention provides the use of
tenofovir alafenamide or a pharmaceutically acceptable salt
thereof, and emtricitabine or a pharmaceutically acceptable salt
thereof, in the manufacture of an oral dosage form disclosed herein
(in particular a tablet) for prevention of HIV infection.
[0286] In certain embodiments, a method of treating a subject with
HIV with the compositions disclosed herein is provided, wherein the
method does not increase the risk of a drug-drug interaction in the
patient. In certain embodiments, a method of treating a subject
with HIV with the compositions disclosed herein is provided,
wherein the method decreases the risk of a drug-drug interaction in
the patient. Exemplary drug-drug interactions include interactions
between the compound of Formula I, tenofovir alafenamide, or
emtricitabine with rifampin, metformin, one or more hormonal
contraceptives or an HCV antiviral agent (e.g., one or more of
sofosbuvir, ledipasvir, velpatasvir, voxilaprevir, grazoprevir,
boceprevir, elbasvir, dasabuvir, ombitasvir, paritaprevir, ABT-530,
and ABT-493). In certain embodiments, a method of treating a
subject with HIV is provided, wherein the subject is administered
one or the compositions disclosed herein, wherein the subject is
also being treated with rifampin, metformin, or an HCV antiviral
agent (e.g., one or more of sofosbuvir, ledipasvir, velpatasvir,
voxilaprevir, grazoprevir, boceprevir, elbasvir, dasabuvir,
ombitasvir, paritaprevir, ABT-530, and ABT-493).
[0287] The methods involve administering an oral dosage form
disclosed herein (in particular a tablet) to the subject, typically
a human, and will generally involve repeated administrations,
typically once daily. The treatment may be prophylactic or
therapeutic treatment.
General
[0288] The term "fed" in relation to administration of a solid oral
dosage form to a human subject means administration of the dosage
form orally under fed conditions (moderate fat meal) e.g.
administration within about 30 minutes of the human consuming a
standardized meal of about 300 to 600 calories and about 10 to
about 15 grams of fat. In some embodiments, "fed" refers to
administration within about 30 minutes of the human consuming a
high fat meal.
[0289] The term "substantially free" in relation to the presence of
a given component within e.g. a composition means that less than 5%
by weight of the composition (e.g. less than 1% by weight of the
composition) is that given component. The word "substantially" does
not exclude "completely" e.g. a composition which is "substantially
free" from Y may be completely free from Y. Where necessary, the
word "substantially" may be omitted from the definition of the
invention.
[0290] The term "segregated" as used in relation to certain
components (e.g. A and B) within a tablet means that those
components are physically discrete such that the presence of one
component (e.g. A) does not substantially affect the stability in
storage of the other component(s) (e.g. B) from which it is
segregated. Typically, when components are segregated in a tablet
then they will be present in separate layers in a multilayer
tablet. By way of example, components A and B may be present in
separate layers in a multilayer tablet, wherein (a) the layer
containing component A is substantially free of component B and (b)
the layer containing component B is substantially free of component
A. The separate layers may be in contact with each other or may be
separated e.g. by one or more additional layers.
[0291] The term "comprise" and variations thereof, such as
"comprises" and "comprising", are to be construed in an open,
inclusive sense, that is as "including, but not limited to".
[0292] The term "between" with reference to two values includes
those two values e.g. the range "between" 10 mg and 20 mg
encompasses e.g. 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20
mg.
[0293] The term "about" used in connection with a quantity is
inclusive of the stated value and has the meaning dictated by the
context (e.g., includes the degree of error associated with
measurement of the particular quantity). For example, in certain
nonlimiting example the term "about" in relation to a numerical
value x refers to x.+-.10%, x.+-.5%, or x.+-.1%.
[0294] "% w/w" means the weight of a component as a percentage of
the total weight of e.g. a layer or dosage form in which the
component is present. For example, a composition comprising "5% w/w
X" refers to a composition in which the weight of component X is 5%
of the total weight of the composition.
[0295] Reference throughout this specification to "one embodiment"
or "an embodiment" means that a particular feature, structure or
characteristic described in connection with the embodiment is
included in at least one embodiment provided herein. Thus, the
appearances of the phrases "in one embodiment" or "in an
embodiment" in various places throughout this specification are not
necessarily all referring to the same embodiment. Furthermore, the
particular features, structures, or characteristics may be combined
in any suitable manner in one or more embodiments.
[0296] The term "pharmaceutically acceptable" with respect to a
substance refers to that substance which is generally regarded as
safe and suitable for use without undue toxicity, irritation,
allergic response, and the like, commensurate with a reasonable
benefit/risk ratio. "Pharmaceutically acceptable" with regard to
excipients includes without limitation any adjuvant, carrier,
excipient, glidant, sweetening agent, diluent, preservative,
dye/colorant, flavor enhancer, surfactant, wetting agent,
dispersing agent, suspending agent, stabilizer, isotonic agent,
solvent, or emulsifier which has been approved by the United States
Food and Drug Administration as being acceptable for use in humans
or domestic animals.
[0297] "Pharmaceutically acceptable salt" refers to a salt of a
compound that is pharmaceutically acceptable and that possesses (or
can be converted to a form that possesses) the desired
pharmacological activity of the parent compound. Such salts include
acid addition salts formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or formed with organic acids such as
acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic
acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic
acid, gluconic acid, lactic acid, maleic acid, malonic acid,
mandelic acid, methanesulfonic acid, 2-napththalenesulfonic acid,
oleic acid, palmitic acid, propionic acid, stearic acid, succinic
acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid,
and the like, and salts formed when an acidic proton present in the
parent compound is replaced by either a metal ion, e.g., an alkali
metal ion, an alkaline earth ion, or an aluminum ion; or
coordinates with an organic base such as diethanolamine,
triethanolamine, N-methylglucamine and the like. Also included in
this definition are ammonium and substituted or quaternized
ammonium salts. Representative non-limiting lists of
pharmaceutically acceptable salts can be found in S. M. Berge et
al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science
and Practice of Pharmacy, R. Hendrickson, ed., 21st edition,
Lippincott, Williams & Wilkins, Philadelphia, Pa., (2005), at
p. 732, Table 38-5, both of which are hereby incorporated by
reference herein.
[0298] As used herein, the term "salts" includes co-crystals. The
term "co-crystal" refers to a crystalline compound comprising two
or more molecular components, e.g. wherein proton transfer between
the molecular components is partial or incomplete.
[0299] The term "solvate" means a molecular complex comprising a
compound and one or more pharmaceutically acceptable solvent
molecules. Examples of solvent molecules include water and 6
alcohols, e.g. ethanol. When the solvate is water, the term
"hydrate" may be used.
[0300] "Treating" and "treatment" of a disease include the
following:
(1) preventing or reducing the risk of developing the disease, i.e.
causing the clinical symptoms of the disease not to develop in a
subject that may be exposed to or predisposed to the disease but
does not yet experience or display symptoms of the disease, (2)
inhibiting the disease, i.e. arresting or reducing the development
of the disease or its clinical symptoms, and (3) relieving the
disease, i.e. causing regression of the disease or its clinical
symptoms. The term "effective amount" refers to an amount that may
be effective to elicit the desired biological or medical response,
including the amount of a compound that, when administered to a
subject for treating a disease, is sufficient to effect such
treatment for the disease. The effective amount will vary depending
on the compound, the disease and its severity and the age, weight,
etc. of the subject to be treated. The effective amount can include
a range of amounts.
EXAMPLES
[0301] The following examples are provided for purposes of
illustration, not limitation.
Example 1--Compound of Formula II Single Agent Tablets
[0302] A formulation (tablet F1) of the compound of Formula II was
prepared by dry granulation. FIG. 5 is a flow diagram illustrating
the preparation of this formulation. The composition of the single
agent formulation is shown in the table below:
TABLE-US-00108 Tablet Formulation F1 Component Mass (mg/tablet) %
w/w/tablet Compound of Formula II 78.7* 26.2 Microcrystalline
cellulose 120 40 Lactose monohydrate 75.8 25.3 Crospovidone 21 7
Sodium Stearyl Fumarate** 4.5 1.5 Total Weight 300 *Equivalent to
75 mg of the Compound of Formula I **Intergranular: 2.25 mg (0.75%;
Extragranular: 2.25 mg (0.75%)
[0303] In the pharmacokinetic studies of Example 3, the tablets of
Formulation F1 were film coated with 12 mg Opadry II Yellow
85F92259. The total weight of the film coated tablets was 312
mg.
[0304] The Compound of Formula II was blended with intergranular
excipients (lactose, microcrystalline cellulose, and crospovidone),
further blended with the intergranular portion of the sodium
stearyl fumarate), roller compacted, milled, and final blended with
the sodium stearyl fumarate to yield a final powder blend for
compression. The final powder blend had a mean particle size of 347
.mu.m with a compressibility index of 21%. The final powder blend
was compressed into tablet cores, which were film-coated as
described above to a target weight gain of 4%.
Example 2--Compound of Formula II/Emtricitabine/Tenofovir
Alafenamide Bilayer Tablets
[0305] A bilayer formulation (tablet F2) of the compound of Formula
II, emtricitabine, and tenofovir alafenamide hemifumarate was
prepared using the method described in Example 8. FIG. 6 is a flow
diagram illustrating the preparation of bilayer tablets. The
composition of the formulation is summarized in the table
below:
TABLE-US-00109 Bilayer tablet F2 (mg/tablet) Compound of
Emtricitabine/ Formula tenofovir alafenamide Ingredient II Layer
hemifumarate Layer Compound of Formula II 78.7* Emtricitabine 200
Tenofovir alafenamide 28.1** hemifumarate Microcrystalline
cellulose 247.8*** 113.1 Croscarmellose sodium 21.2 30.2 Magnesium
Stearate 5.3.sup..dagger. 5.7.sup..dagger..dagger. Layer Weight 353
377 Tablet Core Weight 730 *Equivalent to 75 mg of the Compound of
Formula I **Equivalent to 25 mg tenofovir alafenamide
***Intergranular: 212.5 mg (29.1%); Extragranular: 2.65 mg (0.4%)
.sup..dagger.Intergranular: 2.65 mg (0.4%); Extragranular: 2.65 mg
(0.4%) .sup..dagger..dagger.Intergranular: 2.83 mg (0.4%);
Extragranular 2.83 mg (0.4%)
[0306] In the pharmacokinetic studies of Example 3, the tablets of
Formulation F2 were film coated with 21.9 mg Opadry II Yellow
85F92259 (represented 3% weight gain). The total weight of the film
coated tablets was 752 mg.
[0307] The tablets were manufactured using a dry granulation by
roller compaction process. An emtricitabine/tenofovir alafenamide
final powder blend was manufactured by dry granulation of
emtricitabine and tenofovir alafenamide with excipients
(microcrystalline cellulose, croscarmellose sodium, intergranular
magnesium stearate), followed by blending with extragranular
lubricant (extragranular magnesium stearate). The final powder
blend of the Compound of Formula I was manufactured by dry
granulation of the active component with excipients
(microcrystalline cellulose, croscarmellose sodium, intergranular
magnesium stearate) followed by blending with the extragranular
filler and lubricant (microcrystalline cellulose and extragranular
magnesium stearate). In this study, the emtricitabine/tenofovir
alafenamide final powder blend was compressed as layer 1 and the
final powder blend of the Compound of Formula I was compressed as
layer 2 to give a final bilayer tablet core. The core was film
coated as described above.
Example 2A Emtricitabine/Tenofovir Alafenamide Tablets
[0308] The composition of the emtricitabine/tenofovir alafenamide
(F/TAF) fixed dose combination tablets used in subsequent studies
is shown in the following table:
TABLE-US-00110 Tablet Formulation F3 Emtricitabine/tenofovir
alafenamide 200/25 mg Component (mg/tablet) Intergranular
Emtricitabine 200 Tenofovir Alafenamide Hemifumarate 28.0
Microcrystalline Cellulose 88.7 Croscarmellose Sodium 28.0
Magnesium Stearate 2.6 Extragranular Magnesium Stearate 2.6 Total
Tablet Core Weight 350 Film-Coating Opadry II Blue 85F105057
10.5
[0309] Emtricitabine and tenofovir alafenamide hemifumarate were
co-blended with microcrystalline cellulose and croscarmellose
sodium, followed by lubrication with magnesium stearate. The roller
compaction pre-blend was then roller compacted and milled using an
oscillating mill. The resultant granules were lubricated with
magnesium stearate and compressed into 350 mg tablet cores which
that were subsequently film coated.
Example 3--Pharmacokinetic Studies
[0310] Studies were carried out to assess the pharmacokinetic
profiles of the formulations F1, F2, and F3 of Examples 1, 2, and
2A. A randomized, open-label, multiple-period, fixed-sequence,
crossover study was performed to evaluate the relative
bioavailability of bilayer tablet formulation F2 compared with that
of single agent tablet formulation F1 co-administered
simultaneously with a fixed-dose combination tablet containing
emtricitabine and tenofovir alafenamide (tablet formulation F3).
The bioavailability was evaluated in healthy subjects.
Study Design and Duration of Treatment
[0311] Three single doses of the following tablet formulations were
administered orally during up to 21 days total study duration:
[0312] (a) a fixed dosed combination tablet containing
emtricitabine and tenofovir alafenamide (200/25 mg--Tablet F3) and
a single agent tablet containing the compound of Formula I (75
mg--Tablet F1) administered simultaneously, under fasted conditions
(dosed on day 1; days 2-8 washout); [0313] (b) a fixed dose
combination tablet containing the compound of Formula I,
emtricitabine, and tenofovir alafenamide (75/200/25 mg--Tablet F2)
administered under fasted conditions (dosed on day 9; days 10-16
washout); and [0314] (c) a fixed dose combination tablet containing
the compound of Formula I, emtricitabine, and tenofovir alafenamide
(75/200/25 mg--Tablet F2) administered under fed conditions with a
high-fat meal (dosed on day 17; day 21 discharge).
Criteria for Evaluation
[0315] The following plasma pharmacokinetic parameters were
calculated: C.sub.max, AUC.sub.last, and AUC.sub.inf
Statistical Methods
[0316] Pharmacokinetics: Plasma concentrations and PK parameters
were listed and summarized by analyte and treatment group using
descriptive statistics. In addition, a parametric analysis of
variance using a mixed-effects model appropriate for a crossover
design was fitted to the natural logarithmic transformation of the
PK parameters (AUC.sub.inf, AUC.sub.last, and C.sub.max). Two-sided
90% confidence intervals (CIs) were constructed for the ratio of
geometric least-squares means (GLSMs) of each PK parameter for the
compound of Formula I, emtricitabine, and tenofovir
alafenamide.
Results
[0317] Subject Disposition and Demographics
[0318] A total of 28 subjects were randomized and received at least
1 dose of study drug.
[0319] The results for the first cohort of the clinical study are
summarized in the table below. This table presents the mean (% CV)
values, Geometric Least Squares Mean (GLSM) ratios, and 90% CI
values of the plasma PK parameters AUC.sub.last, AUC.sub.inf, and
C.sub.max for each active ingredient, following administration of
bilayer tablet formulation F2 or the single agent tablet
formulation F1, co-administered with a fixed dose combination of
emtricitabine and tenofovir alafenamide under fasted
conditions.
TABLE-US-00111 Mean (% CV) Compound of Formula I/ Compound of
Formula I F/TAF (75 mg) + (75/200/25 mg) F/TAF (200/25 mg) (Test)
(Reference) % GLSM Ratio PK Parameter (N = 28) (N = 28) (90% CI)
Compound of Formula I AUC.sub.last (h ng/mL) 151,844.0 (26.9)
119,619.4 (26.6) 126.76 (117.82, 136.37) AUC.sub.inf (h ng/mL)
156,637.5 (27.5) 123,174.0 (26.6) 126.82 (117.87, 136.45) C.sub.max
(ng/mL) 7123.9 (21.6) 5593.9 (31.0) 130.72 (119.95, 142.45) FTC
AUC.sub.last (h ng/mL) 11,412.3 (13.5) 11,199.3 (13.7) 101.89
(99.50, 104.33) AUC.sub.inf (h ng/mL) 11,642.8 (13.2) 11,436.4
(13.2) 101.78 (99.45, 104.16) C.sub.max (ng/mL) 2264.3 (22.7)
2153.6 (21.5) 104.86 (97.73, 112.50) TAF AUC.sub.last (h ng/mL)
205.5 (45.5) 223.6 (45.2) 91.62 (82.13, 102.21) AUC.sub.inf (h
ng/mL) 206.8 (45.2) 225.1 (45.0) 91.56 (82.27, 101.91) C.sub.max
(ng/mL) 253.3 (44.2) 276.7 (51.7) 95.47 (79.88, 114.10)
[0320] The total exposure of the compound of Formula I, under
fasted conditions, was approximately 30% higher when dosed in the
bilayer tablet formulation F2, containing two additional
therapeutic agents (TAF and FTC), compared to single agent tablet
formulation F1, co-dosed with a fixed dose combination tablet
containing TAF and FTC (F3). Under fasted conditions, the
AUC.sub.inf and C.sub.max of the compound of Formula I were 27% and
31% higher, respectively, following administration of bilayer
tablet formulation F2 than following administration of single-agent
tablet formulation F1 with the F/TAF fixed dose combination (F3,
200/25 mg). Emtricitabine and tenofovir alafenamide exposure was
similar following administration of bilayer tablet formulation F2
or single-agent tablet formulation F1 with the F/TAF FDC (F3,
200/25 mg).
[0321] Based on the data from this study, a new fixed dose
formulation of the compound of Formula I, emtricitabine, and
tenofovir alafenamide was developed.
[0322] The effect of food on the pharmacokinetics of the compound
of Formula I was also examined in a non-randomized, open label,
crossover, 2 period, fixed sequence, and single dose cohort
consisting of 8 unique subjects. In this study, a single dose of
the compound of Formula I was administered in two periods with
fixed sequence under fasted and fed conditions respectively. A
washout of at least five half-lives was required between fasted and
fed sequences.
[0323] The compound of Formula I was prepared according to percent
weight of the tablet formulation of Example 1, a dose equivalent to
100 mg of the compound of Formula I and excipient amounts adjusted
accordingly to arrive at the designated weight percentages (100
mg/tablet). A single tablet containing the compound of Formula I
(100 mg/tablet) was administered with approximately 240 mL water
after an overnight fast (no food or drink, except water, for at
least 10 hours) on Day 1. Subjects continued to fast until 4 hours
post dose or until collection of the 4-hour postdose blood sample.
On Day 9, A single tablet containing the compound of Formula I (100
mg/tablet) was administered with approximately 240 mL water after
an overnight fast (no food or drink, except water, for at least 10
hours) and within 5 minutes of the subjects finishing a standard
high-fat breakfast (approximately 800 calories with 50% of calories
from fat).
[0324] The evaluation of the effect of food on compound of Formula
I was obtained by comparing AUC.sub.inf, AUC.sub.0-last, and
C.sub.max on Days 1 and 9 under fed and fasted conditions. The
natural log-transformed PK parameters (i.e., AUC.sub.inf,
AUC.sub.0-last, and C.sub.max) were evaluated using a mixed-effects
model with food as a fixed effect and subject as a random effect.
The 90% CI for the geometric least square mean (GLSM) ratios for
fast versus fed was constructed. The statistical comparison of the
pharmacokinetic parameters of the compound of Formula 1 following
single dose administration of this tablet formulation in fed and
fasted states is presented in the table below.
TABLE-US-00112 Mean (% CV) Test Reference Compound of Formula I
Compound of Formula I Compound of Formula I 100 mg Fed 100 mg
Fasted % GLSM Ratio PK Parameter (n = 8) (n = 8) (90% CI)
AUC.sub.inf (hr * ng/mL) 214,146.3 (15.9) 117,777.1 (23.3) 183.97
(152.05, 222.59) AUC.sub.last (hr * ng/mL) 209,259.9 (15.1)
115,681.7 (24.0) 183.58 (151.91, 221.86) C.sub.max (ng/mL) 11,268.8
(15.1) 5885.0 (34.9) 200.69 (165.93, 242.74)
[0325] The Table above presents the GLSM ratios and associated 90%
confidence intervals (CIs) for the test (fed) versus reference
(fasted) treatments for the primary plasma PK parameters of the
compound of Formula I. Administration of a single dose of the
compound of Formula I 100 mg with food (high-calorie/high-fat
breakfast) increased the GLSM values of C.sub.max and AUC.sub.inf
101% (90% CI of GLSM ratio 165.93% to 242.74%) and 84% (90% CI of
GLSM ratio 152.05% to 222.59%), respectively. There were no
apparent changes in clearance and t.sub.1/2 following
administration with food, indicating that food enhanced the
bioavailability of the compound of Formula I by improving its
solubility and/or absorption.
[0326] The effect of food on the PK of the compound of formula I,
emtricitabine, and tenofovir alafenamide when administered as the
tablet formulation F2 tablet was evaluated in the clinical study
described above (The randomized, open-label, multiple-period,
fixed-sequence, crossover study involving 28 subjects comparing
bilayer tablet formulation F2 with that of single agent tablet
formulation F1 co-administered simultaneously with a fixed-dose
combination tablet containing emtricitabine and tenofovir
alafenamide (tablet formulation F3).
[0327] The mean (% CV) values, GLSM ratios, and 90% CI values of
the plasma for PK parameters AUC.sub.last, AUC.sub.inf, and
C.sub.max for the compound of Formula I, emtricitabine, and
tenofovir alafenamide following administration of tablet
formulation F1 under fasted conditions or with a high-fat meal are
presented in the following table.
TABLE-US-00113 Mean (% CV) Compound of Formula I/ Compound of
Formula I/ F/TAF F/TAF (75/200/25 mg) (75/200/25 mg) (High-Fat
Meal; Test) (Fasted; Reference) % GLSM Ratio PK Parameter (N = 28)
(N = 28) (90% CI) Compound of Formula I AUC.sub.last (h ng/mL)
216,733.1 (23.4) 151,844.0 (26.9) 144.45 (134.26, 155.40)
AUC.sub.inf (h ng/mL) 226,142.1 (24.9) 156,637.5 (27.5) 145.88
(135.58, 156.95) C.sub.max (ng/mL) 8941.1 (16.9) 7123.9 (21.6)
126.74 (116.30, 138.12) FTC AUC.sub.last (h ng/mL) 11,483.0 (15.7)
11,412.3 (13.5) 100.34 (97.99, 102.75) AUC.sub.inf (h ng/mL)
11,706.4 (15.6) 11,641.6 (13.2) 100.25 (97.96, 102.59) C.sub.max
(ng/mL) 1872.5 (20.1) 2264.3 (22.7) 83.18 (77.53, 89.25) TAF
AUC.sub.last (h ng/mL) 315.3 (44.0) 205.5 (45.5) 156.81 (140.57,
174.94) AUC.sub.inf (h ng/mL) 319.7 (43.1) 206.8 (45.2) 158.20
(142.14, 176.08) C.sub.max (ng/mL) 212.2 (49.4) 253.3 (44.2) 83.22
(69.63, 99.46)
[0328] Compared with administration under fasted conditions,
administration of the tablet formulation F2 with a high-fat meal
resulted in a 46% higher AUC.sub.inf and a 27% higher C.sub.max for
the compound of Formula I. The impact of food on emtricitabine and
tenofovir alafenamide exposure was similar to that previously
observed.
[0329] The data presented in the two tables above also demonstrate
that the effect of food on the total exposure of the compound of
Formula I is reduced in bilayer tablet formulation F2, relative to
the single agent tablet formulation F1. The geometric mean ratio of
AUC.sub.inf for the compound of Formula I in single agent tablet
formulation F1 was 1.84, while the geometric mean ratio of
AUC.sub.inf for the compound of Formula I in bilayer tablet
formulation F2 was 1.46. In comparison the geometric mean ratio of
AUC.sub.inf for emtricitabine in to 0.91 and 1.00 for emtricitabine
and 1.75 and 1.58 for tenofovir alafenamide in each formulation
respectively (comparing the emtricitabine and tenofovir alafenamide
exposures of the tablet formulation F2 with that of tablet
formulation F1 codosed with the tablet formulation F3). The
geometric mean ratio of C.sub.max for single agent tablet
formulation F1 was 2.01, while the geometric mean ratio of
C.sub.max for bilayer tablet formulation F2 was 1.27. In
comparison, the geometric mean ratios of C.sub.max for
emtricitabine and tenofovir alafenamide in tablet formulations F1
and F2 were 0.85 and 0.83, respectively. These data indicate that a
fixed dosed combination tablet formulation of the compound of
Formula I, emtricitabine, and tenofovir alafenamide may be taken
without regard to food.
Example 4--Dissolution Studies
[0330] Studies were carried out to assess the dissolution profiles
of tablets F1, F2, and F3-A. Dissolution of the compound of Formula
II was measured using USP Apparatus II, in 250 mL of pH 6.5 fasted
state simulated intestinal fluid (FaSSIF), at 37.degree. C. and
paddle speed of 100 rpm. FaSSIF was prepared by adding simulated
intestinal fluid (SIF) powder (Biorelevant.com) to pH 6.5 phosphate
buffer at approximately 4.48 g/L. Once the powder was dissolved,
the volume of the resulting solution was doubled. In the case of
the single agent tablet formulation F1, dissolution of the compound
of Formula II was measured in the presence of the fixed dose
combination tablet formulation F3 of Example 2A containing
emtricitabine and tenofovir alafenamide hemifumarate. The results
are shown in FIG. 1. These data show that the bilayer formulation
(tablet F2) exhibited enhanced dissolution of the compound of
Formula II, compared to the single agent formulation (tablet F1
codosed with F3). Tablet formulation F3-A was prepared as a single
agent formulation according to the process described in Example 1
according to the table below.
TABLE-US-00114 Tablet F3-A (mg/tablet) Compound of Ingredient
Formula II Layer Compound of Formula II 78.7* Emtricitabine
Tenofovir alafenamide hemifumarate Microcrystalline cellulose
247.8*** Croscarmellose sodium 21.2 Magnesium Stearate
5.3.sup..dagger. Tablet Core Weight 353 *Equivalent to 75 mg of the
Compound of Formula I ***Intergranular 212.5 mg (29.1%);
Extragranular 2.65 mg (0.4%) .sup..dagger.Intergranular: 2.65 mg
(0.4%); Extragranular: 2.65 mg (0.4%)
[0331] As shown above, Tablet F3-A used the composition (excipient
selection and quantities) of the Compound of Formula II Layer of
Example 2 (F2). FIG. 1 further demonstrates that Tablet formulation
F2 exhibited enhanced dissolution of the compound of Formula II
compared to Tablet formulations F1 and F3-A. The total percentage
of the compound of Formula II dissolved from formulation F1 and
F3-A was comparable at approximately 60%. The total amount of the
compound of Formula II dissolved from formulation F2 was
approximately 10% higher.
[0332] In a second study, dissolution of the compound of Formula II
was measured using fed state simulated intestinal fluid (FeSSIF) as
dissolution medium. FeSSIF was prepared by adding simulated
intestinal fluid (SIF) powder (Biorelevant.com) to pH 5.0 phosphate
buffer at approximately 22.405 g/L. Once the power was dissolved,
the volume of the resulting solution was doubled. In this study,
dissolution of the compound of Formula II was measured using USP
Apparatus II, in 250 mL of pH 5.5 fed simulated intestinal fluid,
at 37.degree. C. and paddle speed of 100 rpm. As in the previous
study using fasted simulated intestinal fluid, the single agent
tablet formulation F1 was tested in the presence of a second tablet
formulation containing emtricitabine and tenofovir alafenamide
hemifumarate (tablet F3). The results are shown in FIG. 2. These
data also show that the bilayer formulation (tablet F2) exhibited
enhanced dissolution of the compound of Formula II, compared to the
single agent formulation (tablet F1).
Example 5--Excipient Studies
[0333] To further assess the effect of specific excipients on
dissolution of the compound of Formula I, three additional bilayer
tablet formulations were prepared, F4, F5, and F6. Tablet
formulation F4 is similar to tablet formulation F2, with
croscarmellose sodium being replaced with crospovidone. Likewise,
tablet formulation F5 is similar to tablet formulation F2, with
magnesium stearate being replaced with sodium stearyl fumarate.
Finally, tablet formulation F6 is similar to tablet formulation F2,
with both croscarmellose sodium and magnesium stearate being
replaced with crospovidone and sodium stearyl fumarate,
respectively. Tablets F4, F5, and F6 were prepared using the method
described in Example 8.
TABLE-US-00115 Emtricitabine/ Bilayer tablet Bilayer tablet Bilayer
tablet tenofovir alafenamide F4 F5 F6 hemifumarate Layer Compound
of Formula I Layer Ingredient (mg/tablet) (mg/tablet) Emtricitabine
200 Tenofovir alafenamide 28.1 hemifumarate Compound of Formula II
78.7 78.7 78.7 Microcrystalline cellulose 113 244 248 244
Croscarmellose sodium 30.2 21.2 Crospovidone 24.7 24.7 Magnesium
Stearate 5.7 5.3 Sodium Stearyl Fumarate 5.3 5.3 Layer Weight 377
353 353 353 Tablet Core Weight 730 730 730
[0334] FIG. 3 shows the results of dissolution studies performed on
tablet formulations F4, F5, and F6, as well as tablet formulation
F1 and F2. These data demonstrate that the substitution of each
excipient enhances the dissolution of the compound of Formula
I.
Example 6--Compound of Formula I/Emtricitabine/Tenofovir
Alafenamide Bilayer Tablets--50 mg Dose
[0335] As a result of the higher in vivo exposure of the compound
of Formula I that was observed in the pharmacokinetic studies, a
bilayer formulation (tablet F7) of the compound of Formula II,
emtricitabine, and tenofovir alafenamide hemifumarate was prepared
incorporating a lower dose of the compound of Formula I. Tablet
formulation F7 was prepared as described previously, i.e., using
the method described in Example 8. The composition of the
formulation is summarized in the table below:
TABLE-US-00116 Bilayer tablet F7 (mg/tablet) Compound
Emtricitabine/ of Formula tenofovir alafenamide Ingredient II Layer
hemifumarate Layer Compound of Formula II 52.5* Emtricitabine 200
Tenofovir alafenamide 28** hemifumarate Microcrystalline cellulose
246.3 113.2 Croscarmellose sodium 19.4 30.2 Magnesium Stearate 4.9
5.7 Layer Weight 323 377 Tablet Core Weight 700 Opadry II Brown
85F165072 21 Film Coated Tablet 721 *Equivalent to 50 mg of the
Compound of Formula I **Equivalent to 25 mg tenofovir
alafenamide
Example 7--Compound of Formula I Single Agent Tablets (50 mg)
[0336] Dissolution studies were performed comparing the 50 mg dose
bilayer tablet F7 with a 50 mg single agent tablet.
[0337] A 50 mg formulation (tablet F8) of the compound of Formula
II was prepared in a similar manner as tablet formulation F1 of
Example 1. The composition of the single agent formulation is shown
in the table below:
TABLE-US-00117 Tablet Formulation F8 Component Mass (mg/tablet) %
w/w/tablet Compound of Formula II 52.5 26.2 Microcrystalline
cellulose 80 40 Lactose 50.5 25.3 Crospovidone 14 7 Sodium Stearyl
Fumarate 3 1.5 Total Weight 200
[0338] FIG. 4 shows the dissolution of 50 mg bilayer tablet
formulation (fixed dose combination) F7 and 50 mg single agent
tablet formulation F8. Dissolution of the compound of Formula II
was measured using USP Apparatus II, in 333 mL of pH 6.5 FaSSIF, at
37.degree. C. and paddle speed of 100 rpm. Two tablets of each
tablet formulation, F7 and F8 were tested. As in Example 3, in the
case of the single agent tablet formulation F8, dissolution of the
compound of Formula II was measured in the presence of the fixed
dose combination tablet formulation of Example 2A containing
emtricitabine and tenofovir alafenamide hemifumarate. These data
show that the 50 mg bilayer formulation (tablet F7) exhibited
enhanced dissolution of the compound of Formula II, compared to the
single agent formulation (tablet F8).
Example 8--Manufacturing Process
[0339] The manufacturing/packaging procedure for the compound of
Formula II/emtricitabine/tenofovir alafenamide hemifumarate tablets
is divided into five unit processes: [0340] 1. mixing of the
compound of Formula II drug substance with intergranular
excipients, roller compaction or slugging, milling, and blending
with extragranular excipients to yield the final powder blend for
the compound of Formula II; [0341] 2. mixing of emtricitabine and
tenofovir alafenamide hemifumarate drug substances with
intergranular excipients, dry granulation, milling, and blending
with extragranular excipients to yield emtricitabine/tenofovir
alafenamide hemifumarate final powder blend; [0342] 3. tablet
compression to yield bilayer tablet cores; [0343] 4. tablet
film-coating to yield film-coated tablets; and [0344] 5.
packaging.
[0345] The manufacturing process steps to produce the final drug
product are detailed below.
Final Powder Blend for the Compound of Formula II (Dispensing,
Blending, Dry Granulation, Milling, Final Blending)
[0346] 1. Weigh the compound of Formula II and the excipients
(microcrystalline cellulose and croscarmellose sodium). Correct the
weight of the compound of Formula II based on the drug content
factor (DCF), with a concomitant reduction in the weight of
microcrystalline cellulose. [0347] 2. Blend in intergranular
portion of magnesium stearate to the tumble blender and blend.
[0348] 3. Dry granulate the resulting blend using a roller
compactor or slug the resulting blend and mill. [0349] 4. Add
extragranular microcrystalline cellulose and magnesium stearate and
blend.
Emtricitabine/Tenofovir Alafenamide Hemifumarate Final Powder Blend
(Dispensing, Blending, Dry Granulation, Milling, Final
Blending)
[0349] [0350] 5. Weigh emtricitabine and tenofovir alafenamide
hemifumarate drug substances and excipients (microcrystalline
cellulose and croscarmellose sodium). Adjust the weight of
emtricitabine and tenofovir alafenamide hemifumarate drug
substances based on their corresponding DCF, with a concomitant
adjustment to the weight of microcrystalline cellulose. [0351] 6.
Blend in emtricitabine and tenofovir alafenamide hemifumarate drug
substance, microcrystalline cellulose, and croscarmellose sodium to
a tumble blender and blend. [0352] 7. Blend in intergranular
portion of magnesium stearate to the tumble blender and blend.
[0353] 8. Dry granulate the resulting blend using a roller
compactor or slug the resulting blend and mill. [0354] 9. Blend in
the extragranular portion of magnesium stearate.
Tableting
[0354] [0355] 10. Compress the final powder blend of the compound
of Formula II as the first layer and the emtricitabine/tenofovir
alafenamide hemifumarate final powder blend as the second layer,
with an appropriate main compression force to achieve a target
hardness of 17 kP (range: 14 to 20 kP). For tablet formulations
containing 50 mg of the compound of Formula II, the final powder
blend is compressed to a target layer weight of 323 mg using a
target total tablet weight of 700 mg. For tablet formulations
containing 75 mg of the compound of Formula II, the final powder
blend is compressed to a target layer weight of 353 mg using a
target total tablet weight of 730 mg.
Film-Coating
[0355] [0356] 11. Prepare a suspension of Opadry.RTM. II Brown
85F165072 (for tablets containing 50 mg compound of Formula I) or
Opadry.RTM. II Yellow 85F92259 (for tablets containing 75 mg
compound of Formula I). Film-coat the tablet cores to achieve the
target tablet weight gain of 3% (range 2-4%). Dry film-coated
tablets prior to cooling and discharge.
Example 9--Pharmacokinetic Studies--Cohort 2
[0357] The pharmacokinetic study of Example 3 was continued with a
second treatment group (cohort) to assess the pharmacokinetic
profile of formulation F7 of Example 7 compared with that of
formulation F2.
Study Design and Duration of Treatment
[0358] Four single doses of the following tablet formulations were
administered once per day orally during 36 days total study
duration: [0359] (a) a fixed dosed combination tablet containing
emtricitabine and tenofovir alafenamide (200/25 mg--Tablet F3) and
a single agent tablet containing the compound of Formula I (75
mg--Tablet F1) administered simultaneously, under fasted conditions
(Treatment A) (dosed on day 1; days 2-8 washout); [0360] (b) a
fixed dose combination tablet containing the compound of Formula I,
emtricitabine, and tenofovir alafenamide (50/200/25 mg--Tablet F2)
administered under fasted conditions (Treatment D) (dosed on day 9;
days 10-16 washout); and [0361] (b) a fixed dose combination tablet
containing the compound of Formula I, emtricitabine, and tenofovir
alafenamide (50/200/25 mg--Tablet F2) administered under fed
conditions with a high-fat meal (Treatment E) (dosed on day 17;
days 18-24 washout); [0362] (c) a fixed dose combination tablet
containing the compound of Formula I, emtricitabine, and tenofovir
alafenamide (50/200/25 mg--Tablet F2) administered under fed
conditions with a moderate-fat meal (Treatment F) (dosed on day 25;
day 29 discharge).
Criteria for Evaluation
[0363] The following plasma pharmacokinetic parameters were
calculated: AUC.sub.last, AUC.sub.inf, % AUC.sub.exp, C.sub.max,
C.sub.last, T.sub.max, T.sub.last, CL/F, V.sub.z/F, and
t.sub.1/2.
Statistical Methods
[0364] Pharmacokinetics: Individual subject concentration data and
individual subject PK parameters for each analyte (compound of
Formula 1, FTC, and TAF) were listed and summarized using
descriptive statistics by treatment group (cohort) and treatment.
Summary statistics were determined for both individual subject
concentration data by time point, cohort, and treatment and
individual subject PK parameters by cohort and treatment. Also, the
geometric mean, 95% confidence interval (CI), and the mean, and
standard deviation (SD) of the natural log-transformed values were
presented for individual subject PK parameter data. The sample size
for each time point was based on the number of subjects with
nonmissing concentration data at that time point. The number of
subjects with concentration below the level of quantitation (BLQ)
was presented for each time point.
[0365] Statistical comparisons of the natural log-transformed PK
parameters for each analyte and treatment comparison of interest
were performed. The statistical modelling was based on the PK
Analysis set for the analyte under evaluation. For each analyte,
all subjects with available data for the PK parameter under
evaluation were included in the modelling. The statistical
comparisons using Treatment A as a reference only used data from
this cohort, not from the earlier cohort of Example 3 (i.e.,
Treatment A was not pooled).
[0366] For each analyte and each PK parameter, a parametric (normal
theory) mixed-effects ANOVA model was fitted to the natural
log-transformed values of the PK parameter under evaluation. The
statistical model included treatment as a fixed effect and subject
as a random effect.
[0367] A total of 27 subjects completed the second treatment group
of the study.
Results
[0368] Plasma pharmacokinetic parameters for each analyte are
presented below. This table presents the mean (% CV) values,
Geometric Least Squares Mean (GLSM) ratios, and 90% CI values of
the plasma PK parameters AUC.sub.last, AUC.sub.inf, and C.sub.max
for each active ingredient, following administration of bilayer
tablet formulation F7 and monolayer tablet formulation F1
coadministered with F/TAF formulation F3, under fasted
conditions.
TABLE-US-00118 Mean (% CV) Formulation F7 Formulation F1 + F3
Compound of Formula Compound of Formula (75 1/F/TAF (50/200/25 mg),
mg) + F/TAF (200/25 mg)), fasted fasted % GLSM Ratio (90% CI)
(Test) (N = 27) (Reference) (N = 28) (Test/Reference) Compound of
Formula I PK Parameter AUC.sub.last (hr ng/mL) 109,061.4 (21.0)
142,396.6 (30.5) 78.46 (73.38, 83.89) AUC.sub.inf (hr ng/mL)
112,619.6 (21.9) 146,931.6 (31.1) 78.56 (73.44, 84.04) C.sub.max
(ng/mL) 5228.1 (16.9) 6791.1 (26.4) 78.07 (73.41, 83.01) FTC PK
Parameter AUC.sub.last (hr ng/mL) 10,652.9 (13.6) 11,035.5 (14.4)
96.52 (93.95, 99.15) AUC.sub.inf (hr ng/mL) 10,873.9 (13.6)
11,234.6 (14.2) 96.76 (94.22, 99.37) C.sub.max (ng/mL) 2220.4
(30.1) 2166.4 (27.0) 102.36 (93.85, 111.64) TAF PK Parameter.sup.a
AUC.sub.last (hr ng/mL) 207.1 (46.5) 236.7 (45.3) 85.37 (75.24,
96.85) AUC.sub.inf (hr ng/mL) 208.8 (46.3) 238.3 (45.0) 85.48
(75.33, 97.00) C.sub.max (ng/mL) 249.2 (51.6) 291.9 (55.4) 84.17
(67.59, 104.81)
[0369] In particular, these data confirmed that the exposure of the
compound of Formula I in Formulation F7 was proportionally lower
than that observed in Formulation F2 and were consistent with
predicted exposures for the revised dose. These data were
consistent with the modelling of earlier clinical data confirming
that these exposures provided anti-HIV antiviral efficacy. FTC and
TAF exposure were similar between Formulation F7 and Formulation F2
coadministered with F3; TAF C.sub.max was slightly lower (by
approximately 16%) for Formulation F7 than for the coadministration
of F2 and F3.
[0370] The effect of food on the pharmacokinetics of the compound
of Formula I, emtricitabine and tenofovir alafenamide when
administered in formulation F7 was also examined in a further
treatment group of the above described clinical study.
[0371] The mean (% CV) values, GLSM ratios, and 90% CI values of
the plasma for PK parameters AUC.sub.last, AUC.sub.inf, and
C.sub.max for the compound of Formula I, emtricitabine, and
tenofovir alafenamide following administration of tablet
formulation F7 under fasted conditions or with a high-fat meal and
with a moderate-fat meal are presented in the following table.
TABLE-US-00119 Mean (% CV) Compound of Formula Compound of Formula
I/F/TAF (50/200/25 mg) I/F/TAF (50/200/25 mg) high fat meal (Test)
fasted (Reference) % GLSM Ratio (90% CI) (N = 27) (N = 27)
(Test/Reference) Compound of Formula I PK Parameter AUC.sub.last
(hr ng/mL) 135,117.3 (21.1) 109,061.4 (21.0) 123.96 (115.91,
132.57) AUC.sub.inf (hr ng/mL) 140,032.4 (21.8) 112,619.6 (21.9)
124.41 (116.27, 133.11) C.sub.max (ng/mL) 5936.3 (18.3) 5228.1
(16.9) 113.23 (106.45, 120.43) FTC PK Parameter AUC.sub.last (hr
ng/mL) 10,213.0 (12.0) 10,652.9 (13.6) 96.02 (93.47, 98.65)
AUC.sub.inf (hr ng/mL) 10,467.0 (11.9) 10,873.9 (13.6) 96.41
(93.88, 99.02) C.sub.max (ng/mL) 1881.1 (24.2) 2220.4 (30.1) 85.52
(78.37, 93.31) TAF PK Parameter.sup.a AUC.sub.last (hr ng/mL) 310.3
(34.9) 207.1 (46.5) 162.62 (143.10, 184.80) AUC.sub.inf (hr ng/mL)
318.4 (32.8) 208.8 (46.3) 166.55 (146.54, 189.29) C.sub.max (ng/mL)
236.6 (65.1) 249.2 (51.6) 91.71 (73.46, 114.49) Compound of Formula
I PK Parameter AUC.sub.last (hr ng/mL) 135,217.3 (22.9) 109,061.4
(21.0) 123.56 (115.53, 132.14) AUC.sub.inf (hr ng/mL) 140,197.7
(23.6) 112,619.6 (21.9) 124.06 (115.95, 132.74) C.sub.max (ng/mL)
6279.6 (18.3) 5228.1 (16.9) 119.90 (112.72, 127.53) FTC PK
Parameter AUC.sub.last (hr ng/mL) 10,738.3 (9.8) 10,652.9 (13.6)
101.17 (98.48, 103.94) AUC.sub.inf (hr ng/mL) 10,973.3 (9.5)
10,873.9 (13.6) 101.33 (98.66, 104.06) C.sub.max (ng/mL) 1998.9
(18.4) 2220.4 (30.1) 91.84 (84.17, 100.21) TAF PK Parameter.sup.a
AUC.sub.last (hr ng/mL) 290.6 (41.3) 207.1 (46.5) 148.20 (130.41,
168.41) AUC.sub.inf (hr ng/mL) 293.1 (40.9) 208.8 (46.3) 148.23
(130.42, 168.47) C.sub.max (ng/mL) 251.1 (66.7) 249.2 (51.6) 99.04
(79.33, 123.65) .sup.aN = 28 for the Reference group
[0372] Compared with administration under fasted conditions,
administration of the tablet formulation F7 with a high-fat meal
resulted in a 24% higher AUC.sub.inf and a 13% higher C.sub.max for
the compound of Formula I. Administration of a moderate fat meal,
resulted in a 24% higher AUC.sub.inf and a 20% higher C.sub.max for
the compound of Formula I. The impact of food on emtricitabine and
tenofovir alafenamide exposure was similar to that previously
observed.
[0373] These data confirm that a fixed dosed combination tablet
formulation of the compound of Formula I, emtricitabine, and
tenofovir alafenamide may be taken without regard to food.
Example 10--Compression Studies
[0374] To further investigate the properties of the compositions,
the following studies investigated blend compressibility and layer
adhesion.
[0375] First, various final blend compositions including the
Compound of Formula I (as a sodium salt, i.e., the Compound of
Formula II) were prepared with varying levels of intergranular or
extragranular lactose is shown in the table below.
TABLE-US-00120 Compound of Formula II: Final Powder Blends
Containing Lactose Tablet Formulation Components F9 F10 F11 F12 F13
F14 Intergranular % w/w Compound of 16.24 16.24 16.24 16.24 14.86
14.86 Formula II Microcrystalline 46.25 56.25 56.25 56.25 69.12
60.63 Cellulose Lactose 20.00 NA NA NA 0.00 8.50 Croscarmellose
6.00 6.00 6.00 6.00 5.49 5.49 Sodium Magnesium 0.75 0.75 0.75 0.75
0.69 0.69 Stearate Extragranular % w/w Microcrystalline 10.00 10.00
5.00 15.00 9.15 9.15 Cellulose Lactose NA 10.00 15.00 5.00 NA NA
Magnesium 0.75 0.75 0.75 0.75 0.69 0.69 Stearate Layer weight 323
323 323 323 353 353 (mg)
[0376] Next, final blend compositions of the Compound of Formula II
with varying amounts of magnesium stearate ranging from 0.75% to
0.5% were prepared as shown on the following table:
TABLE-US-00121 Compound of Formula I: Final Powder Blends with
Varying Levels of Magnesium Stearate Tablet Formulation Components
F15 F16 F17 F18 F19 F20 Intergranular % w/w Compound of 16.24 16.24
16.24 16.24 16.24 16.24 Formula II Microcrystalline 66.25 66.30
66.40 66.40 66.50 66.75 Cellulose Croscarmellose 6.00 6.00 6.00
6.00 6.00 6.00 Sodium Magnesium 0.75 0.70 0.60 0.60 0.50 0.50
Stearate Extragranular % w/w Microcrystalline 10.00 10.00 10.00
10.00 10.00 10.00 Cellulose Magnesium 0.75 0.75 0.75 0.75 0.75 0.5
Stearate Layer weight 323 323 323 323 323 323 (mg)
[0377] Finally, final blend compositions containing emtricitabine
and tenofovir alafenamide were prepared with varying amounts of
magnesium stearate ranging from 0.75% to 0.5% as shown in the table
below:
TABLE-US-00122 Quantitative Compositions of F/TAF Final Powder
Blends Tablet Formulation Components F21 F22 F23 F24 Intergranular
% w/w Tenofovir Alafenamide Hemifumarate 7.5 7.5 7.5 7.5
Emtricitabine 53.1 53.1 53.1 53.1 Microcrystalline Cellulose 29.9
30.4 30 30.2 Croscarmellose Sodium 8.0 8.0 8.0 8.0 Magnesium
Stearate 0.75 0.50 0.70 0.60 Extragranular % w/w Magnesium Stearate
0.75 0.50 0.70 0.60 Layer Weight (mg) 377 377 377 377
[0378] Altering magnesium stearate content was studied to evaluate
the impact on the compound of Formula I and emtricitabine/tenofovir
alafenamide blend compressibility and layer adhesion. Formulations
were also monitored for punch filming and sticking.
[0379] Fourteen combinations of the final powder blends described
in the above tables were prepared as summarized in the table below.
Critical tamp force was determined for all fourteen
combinations.
TABLE-US-00123 Compression Study Critical Layer 1 Tamp Force
Results Tablet Tablet Formu- Formu- Formu- Critical lation lation
lation Tamp Force Combination Layer 1 Layer 2 (kN) Observation A*
F21 F15 1.0 Layers adhered B* F21 F9 <1.5 Delamination C* F21
F10 <1.5 Delamination D* F21 F11 <1.5 Delamination E* F21 F12
<1.5 Delamination F* F21 F13 <1.5 Delamination G* F21 F14
<1.5 Delamination H F15 F21 1.5 Delamination I F15 F22 2.0
Layers adhered J F16 F23 2.0 Layers adhered K F17 F24 1.5 Layers
adhered L F18 F22 2.0 Layers adhered M F19 F22 2.5 Layers adhered,
sticking N F20 F22 2.5 Layers adhered, sticking *Note F/TAF as
layer 1 and Compound of Formula I as layer 2 IG: Intergranular EG:
Extragranular MgSt Magnesium Stearate
[0380] Combination A represents layer order and composition used as
baseline for comparison of other compositions. The tablet
formulation of each layer corresponds to the corresponding layer of
tablet formulation F7. One objective was to investigate whether it
was possible to improve on the critical tamp force of 1.0 kN
observed for Combination A.
[0381] Combinations B-G represent studies in which lactose was
included in the layer including the Compound of Formula I to
investigate evaluate layer adhesion. Combination G included 20%
lactose in the intergranular portion, with none in the
extragranular portion. The ratio of lactose to microcrystalline
cellulose ranged from 1:1, 3:1, 1:3 in Combinations C, D, and E,
respectively. Combination G included 20 mg lactose in the
intergranular portion. Delamination was observed at 1.5 kN for
Combinations B-G. As a result, lower tamp forces were not further
investigated. When layer order was reversed (Combination H),
delamination did not occur at 1.0 kN but was observed at 1.5 kN
using the layer compositions of Combination A.
[0382] In Combinations I-N, varying the amount of magnesium
stearate in each layer was investigated to determine the effect on
compressibility and layer adhesion. Intergranular magnesium
stearate was 0.75%, 0.70% and 0.60% in the Compound of Formula I
layer of Combinations I, J, and K, respectively. Total magnesium
stearate content in the F/TAF layer of each of Combinations I, J,
and K was 1.0%, 1.4% and 1.2%%, respectively. Intergranular
magnesium stearate was 0.6% and 0.5% in the Compound of Formula I
layer of Combinations L and M, respectively (with 0.75%
extragranular magnesium stearate in each). Combination N has the
lowest overall level of magnesium stearate in both layers (1.0% in
each layer).
[0383] It was found that reducing magnesium stearate from 0.75% to
0.5% in each of the intergranular and extragranular portions the
emtricitabine/tenofovir alafenamide layer increased critical tamp
force to 2.0 kN (combination I). Critical tamp force could be
further improved to 2.5 kN when magnesium stearate was reduced to
0.5% extragranular and/or intergranular in the layer containing the
Compound of Formula I (combinations M and N). However, despite
gaining an increase in critical tamp force, decreasing magnesium
stearate to 0.5% in each component of the powder blend containing
the Compound of Formula 1 had a negative effect on sticking.
Intermediate changes in magnesium stearate (Combinations J-L) had
no further improvement over combination I. As a result, magnesium
stearate level was decreased in the emtricitabine/tenofovir
alafenamide layer only (formulation combination I). A critical
layer 1 tamp force of 1377 N was ultimately determined. The table
below summarizes the composition of Formulation I.
[0384] Thus, the addition of intergranular or extragranular lactose
to the layer containing the Compound of Formula I had little to ono
effect on layer adhesion. Decreasing magnesium stearate from each
of final powder blends improved compressibility.
Quantitative Composition of Combination Formulation I
TABLE-US-00124 [0385] Components Quantity per Tablet (mg) w/w (%)
Compound of Formula I Layer Compound of Formula II.sup.a
52.5.sup.a, b 7.5 Microcrystalline Cellulose 246.3 35.2
Croscarmellose Sodium 19.4 2.8 Magnesium Stearate 4.9 0.7 Subtotal
323 46.1 F/TAF Layer Emtricitabine.sup.c 200.0.sup.c 28.6 Tenofovir
Alafenamide Fumarate.sup.c 28.0.sup.c, d 4.0 Microcrystalline
Cellulose 115.0 16.4 Croscarmellose Sodium 30.2 4.3 Magnesium
Stearate 3.8 0.5 Subtotal 377 53.9 Total Bilayer Tablet Core Weight
700 100 Film Coat Opadry II Brown 85F165072.sup.e 21.sup.f 3.sup.f
Purified Water.sup.g --.sup.g --.sup.g .sup.aThe quantity used is
adjusted on the basis of the purity of each batch of Compound of
Formula II with a concomitant adjustment of the quantity of
microcrystalline cellulose. .sup.bEquivalent to 50 mg of Compound
of Formula I free acid. .sup.cThe quantity used is adjusted on the
basis of the purity of each batch of emtricitabine and tenofovir
alafenamide hemifumarate with a concomitant adjustment of the
quantity of microcrystalline cellulose. .sup.dEquivalent to 25 mg
of tenofovir alafenamide free base. .sup.eOpadry II Brown 85F165072
contains polyvinyl alcohol, USP (40.0% w/w); titanium dioxide, USP
(22.0% w/w); polyethylene glycol, NF (20.2% w/w); talc, USP (14.8%
w/w); iron oxide red, NF (2.4% w/w); iron oxide black, NF (0.6%
w/w). .sup.fRepresents a theoretical weight gain of 3% w/w (range
2% to 4% w/w) onto the tablet core weight. .sup.gSufficient
purified water is used for film coating and is removed during the
process
[0386] All publications, patents and patent applications are
incorporated by reference in their entirety, as though individually
incorporated by reference. The invention has been described with
reference to various specific and preferred embodiments and
techniques. However, it should be understood that many variations
and modifications may be made while remaining within the spirit and
scope of the invention.
* * * * *