U.S. patent application number 10/540794 was filed with the patent office on 2006-11-02 for compositions and methods for combination antiviral therapy.
Invention is credited to Terrence C. Dahl, Mark M. Menning, Reza Oliyai.
Application Number | 20060246130 10/540794 |
Document ID | / |
Family ID | 32776014 |
Filed Date | 2006-11-02 |
United States Patent
Application |
20060246130 |
Kind Code |
A1 |
Dahl; Terrence C. ; et
al. |
November 2, 2006 |
Compositions and methods for combination antiviral therapy
Abstract
The present invention relates to therapeutic combinations of
[2-(6-amino-purin-9 yl)-1-methyl-ethoxymethyl]-phosphonic acid
diisopropoxycarbonyloxymethyl ester (tenofovir disoproxil fumarate,
Viread.RTM.) and (2R,5S,cis)-4-amino-5-fluoro-1-(2
hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one
(emtricitabine, Emtriva.TM., (-)-cis FTC) and their physiologically
functional derivatives. The combinations may be useful in the
treatment of HIV infections, including infections with HIV mutants
bearing resistance to nucleoside and/or non-nucleoside inhibitors.
The present invention is also concerned with pharmaceutical
compositions and formulations of said combinations of tenofovir
disoproxil fumarate and emtricitabine, and their physiologically
functional derivatives, as well as therapeutic methods of use of
those compositions and formulations.
Inventors: |
Dahl; Terrence C.; (SAN
FRANCISCO, CA) ; Menning; Mark M.; (San Francisco,
CA) ; Oliyai; Reza; (San Carlos, CA) |
Correspondence
Address: |
GILEAD SCIENCES INC
333 LAKESIDE DR
FOSTER CITY
CA
94404
US
|
Family ID: |
32776014 |
Appl. No.: |
10/540794 |
Filed: |
January 13, 2004 |
PCT Filed: |
January 13, 2004 |
PCT NO: |
PCT/US04/00832 |
371 Date: |
March 20, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60440308 |
Jan 14, 2003 |
|
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|
60440246 |
Jan 14, 2003 |
|
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Current U.S.
Class: |
424/464 ;
514/269; 514/81 |
Current CPC
Class: |
A61K 9/2013 20130101;
A61P 31/00 20180101; A61K 31/675 20130101; A61K 31/683 20130101;
A61K 45/06 20130101; A61P 31/18 20180101; A61P 31/12 20180101; A61P
43/00 20180101; A61K 9/2054 20130101; A61K 9/2059 20130101; A61K
9/2009 20130101; A61K 31/513 20130101; A61K 9/2018 20130101; A61K
31/7076 20130101; A61K 31/675 20130101; A61K 2300/00 20130101; A61K
31/7076 20130101; A61K 2300/00 20130101; A61K 31/513 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
424/464 ;
514/081; 514/269 |
International
Class: |
A61K 31/675 20060101
A61K031/675; A61K 31/513 20060101 A61K031/513; A61K 9/20 20060101
A61K009/20 |
Claims
1-58. (canceled)
59. A method comprising administering a therapeutically effective
amount of a composition comprising
[2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid
diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil
fumarate) and
(2R,5S,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-
-pyrimidin-2-one (emtricitabine) to a patient in need of antiviral
therapy consisting of anti-HIV therapy.
60. The method of claim 59 wherein the anti-HIV active ingredients
in the composition consist of tenofovir disoproxil fumarate and
emtricitabine.
61. The method of claim 60 wherein the composition comprises about
300 mg of tenofovir disoproxil fumarate and about 200 mg of
emtricitabine.
62. The method of claim 59 wherein the amount of the total
tenofovir disoproxil fumarate and emtricitabine in the composition
in relation to carrier material is about 5% to about 95% of the
total composition (weight:weight, exclusive of coating).
63. The method of claim 59 wherein tenofovir disoproxil fumarate
and emtricitabine are present in a tablet.
64. The method of claim 63 wherein tenofovir disoproxil fumarate
and emtricitabine are present in an amount of 300 mg and 200 mg
respectively.
65. The method of claim 59 wherein the manufacture is by wet
granulation.
66. The method of claim 62 wherein the weight ratio of the total of
tenofovir disoproxil fumarate and emtricitabine in the composition
in relation to ingredients other than tenofovir disoproxil fumarate
and emtricitabine is 50:50 (excluding coating).
67. The method of claim 66 wherein the composition comprises in
weight percent (excluding coating) tenofovir disoproxil fumarate
30, emtricitabine 20, pregelatinized starch 5, croscarmellose
sodium 6, lactose monohydrate 8, microcrystalline cellulose 30,
magnesium stearate 1.
68. The method according to claim 59 wherein the composition
further comprises a third active ingredient selected from an HIV
protease inhibitor (PI), an HIV nucleoside reverse transcriptase
inhibitor (NRTI), an HIV non-nucleoside reverse transcriptase
inhibitor (NNRTI), and an HIV integrase inhibitor.
69. The method according to claim 68 wherein the third active
ingredient is selected from the Reyataz, Kaletra, or Sustiva
anti-HIV agents.
70. The method according to claim 59 wherein the composition
further comprises a pharmaceutically acceptable glidant.
71. The method according to claim 70 wherein the glidant is
selected from silicon dioxide, powdered cellulose, microcrystalline
cellulose, metallic stearates, sodium aluminosilicate, sodium
benzoate, calcium carbonate, calcium silicate, corn starch,
magnesium carbonate, asbestos free talc, stearowet C, starch,
starch 1500, magnesium lauryl sulfate, magnesium oxide, and
formulations thereof.
72. The method according to claim 71 wherein the metallic stearates
are selected from calcium stearate, magnesium stearate, zinc
stearate, and formulations thereof.
73. A pharmaceutical formulation comprising
[2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid
diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil
fumarate) and
(2R,5S,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-
-pyrimidin-2-one (emtricitabine).
74. The pharmaceutical formulation according to claim 73 further
comprising one or more pharmaceutically acceptable carriers or
excipients.
75. The pharmaceutical formulation according to claim 74 wherein
the pharmaceutically acceptable carriers or excipients are selected
from pregelatinized starch, croscarmellose sodium, povidone,
lactose monohydrate, microcrystalline cellulose, and magnesium
stearate, and formulations thereof.
76. The pharmaceutical formulation according to claim 74 wherein
the amount of the total tenofovir disoproxil fumarate and
emtricitabine in the formulation in relation to carrier and
excipient material (weight:weight, excluding coating) is about 5%
to about 95% (weight ratio 0.08).
77. The pharmaceutical formulation according to claim 76 wherein
the weight ratio of tenofovir disoproxil fumarate and entricitabine
together: total carrier and excipient in the formulation (excluding
coating) is 500:1000, 400:900, 325:825, 225:725, 200:700, 500:700,
500:670, 500:763, 500:2840 or 500:2270.
78. The pharmaceutical formulation according to claim 77 wherein
the weight ratio (excluding coating) is 0.50, 0.44, 0.39, 0.31,
0.29, 0.71, 0.75, 0.65, 0.18 or 0.22.
79. The pharmaceutical formulation according to claim 76 wherein
the weight ratio (excluding coating) is from 0.18 to 0.75.
80. The pharmaceutical formulation according to claim 73 in
pharmaceutical dosage form.
81. The pharmaceutical formulation according to claim 80 wherein
the pharmaceutical dosage form is a tablet.
82. The pharmaceutical formulation according to claim 73 wherein
tenofovir disoproxil fumarate and emtricitabine are present in a
ratio of about 300:200 by weight.
83. The pharmaceutical formulation according to claim 82 comprising
about 300 mg of tenofovir disoproxil fumarate and about 200 mg of
emtricitabine.
84. The pharmaceutical formulation according to claim 73 suitable
for oral administration.
85. The pharmaceutical formulation according to claim 84 wherein
the pharmaceutical dosage form is a capsule.
86. The pharmaceutical formulation according to claim 73 suitable
for administration once per day to an infected human.
87. A patient pack comprising (a) at least one coformulated
pharmaceutical formulation comprising
[2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid
diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil
fumarate) and
(2R,5S,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-
-pyrimidin-2-one (emtricitabine), and (b) an information insert
containing directions for the use of tenofovir disoproxil fumarate
and emtricitabine in formulation for the treatment of a patient in
need of antiviral treatment consisting of anti-HIV therapy.
88. The patient pack according to claim 87 wherein the
pharmaceutical dosage form is a tablet, caplet, or capsule
comprising 300 mg of tenofovir disoproxil fumarate and 200 mg of
emtricitabine.
89. The pharmaceutical formulation of any of claims 73 or 87 which
further comprises a third antiviral agent.
90. The formulation of claim 89 wherein the third agent is selected
from an HIV protease inhibitor (PI), an HIV nucleoside reverse
transcriptase inhibitor (NRTI), an HIV non-nucleoside reverse
transcriptase inhibitor (NNRTI), and an HIV integrase
inhibitor.
91. The formulation of claim 90 wherein the third antiviral agent
is a PI.
92. The formulation of claim 90 wherein the third antiviral agent
is an NNRTI.
93. The formulation of claim 90 wherein the third antiviral agent
is selected from the Reyataz, Kaletra, or Sustiva anti-HIV
agents.
94. An oral pharmaceutical dosage form comprising tenofovir
disoproxil fumarate, emtricitabine and Reyataz.
95. An oral pharmaceutical dosage form comprising tenofovir
disoproxil fumarate, emtricitabine and Kaletra.
96. An oral pharmaceutical dosage form comprising tenofovir
disoproxil fumarate, emtricitabine and Sustiva.
97. The pharmaceutical formulation of claim 73 comprising in weight
percent (excluding coating) tenofovir disoproxil fumarate 30,
emtricitabine 20, pregelatinized starch 5, croscarmellose sodium 6,
lactose monohydrate 8, microcrystalline cellulose 30, and magnesium
stearate 1.
98. A tablet comprising 300 mg of tenofovir disoproxil fumarate,
200 mg of emtricitabine and carriers and/or excipients sufficient
to produce less than 5% acid degradation of tenofovir disoproxil
fumarate or emtricitabine after six months storage with desiccant
at 40.degree. C./25% relative humidity.
99. An oral dosage form comprising Sustiva, 300 mg tenofovir
disoproxil fumarate, 200 mg of emtriva and pharmaceutically
acceptable carriers or excipients.
Description
[0001] This non-provisional application claims the benefit of
Provisional Application Nos. 60/440,246 and 60/440,308, both filed
Jan. 14, 2003, which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention relates generally to combinations of compounds
with antiviral activity and more specifically with anti-HIV
properties. In particular, it relates to chemically stable
combinations of structurally diverse anti-viral agents.
BACKGROUND OF THE INVENTION
[0003] Human immunodeficiency virus (HIV) infection and related
diseases are a major public health problem worldwide. Human
immunodeficiency virus type 1 (HIV-1) encodes at least three
enzymes which are required for viral replication: reverse
transcriptase (RT), protease (Prt), and integrase (Int). Although
drugs targeting reverse transcriptase and protease are in wide use
and have shown effectiveness, particularly when employed in
combination, toxicity and development of resistant strains have
limited their usefulness (Palella, et al N. Engl. J. Med. (1998)
338:853-860; Richman, D. D. Nature (2001) 410:995-1001). Human
immunodeficiency virus type 1 (HIV-1) protease (Prt) is essential
for viral replication and is an effective target for approved
antiviral drugs. The HIV Prt cleaves the viral Gag and Gag-Pol
polyproteins to produce viral structural proteins (p17, p24, p7 and
p6) and the three viral enzymes. Combination therapy with RT
inhibitors has proven to be highly effective in suppressing viral
replication to unquantifiable levels for a sustained period of
time. Also, combination therapy with RT and Prt inhibitors (PI)
have shown synergistic effects in suppressing HIV replication.
Unfortunately, a high percentage, typically 30 to 50% of patients
currently fail combination therapy due to the development of drug
resistance, non-compliance with complicated dosing regimens,
pharmacokinetic interactions, toxicity, and lack of potency.
Therefore, there is a need for new HIV-1 inhibitors that are active
against mutant HIV strains, have distinct resistance profiles,
fewer side effects, less complicated dosing schedules, and are
orally active. In particular, there is a need for a less onerous
dosage regimen, such as once per day oral dosing, optimally with as
few pills as possible.
[0004] The use of combinations of compounds can yield an equivalent
antiviral effect with reduced toxicity, or an increase in drug
efficacy. Lower overall drug doses can reduce the frequency of
occurrence of drug-resistant variants of HIV. Many different
methods have been used to examine the effects of combinations of
compounds acting together in different assay systems (Furman WO
02/068058). Lower doses predict better patient compliance when pill
burden decreases, dosing schedules are simplified and, optionally,
if synergy between compounds occurs (Loveday, C. "Nucleoside
reverse transcriptase inhibitor resistance" (2001) JAIDS Journal of
Acquired Immune Deficiency Syndromes 26:S10-S24). AZT
(zidovudine.TM., 3'-azido, 3'-deoxythymidine) demonstrates
synergistic antiviral activity in vitro in combination with agents
that act at HIV-1 replicative steps other than reverse
transcription, including recombinant soluble CD4 castanospermine
and recombinant interferon-.alpha.. However, it must be noted that
combinations of compounds can give rise to increased cytotoxicity.
For example, AZT and recombinant interferon-.alpha. have an
increased cytotoxic effect on normal human bone marrow progenitor
cells.
[0005] Chemical stability of combinations of antiviral agents is an
important aspect of co-formulation success and the present
invention provides examples of such combinations.
[0006] There is a need for new combinations of orally-active drugs
for the treatment of patients infected with certain viruses, e.g.
HIV, that provide enhanced therapeutic safety and efficacy, impart
lower resistance, and predict higher patient compliance.
SUMMARY OF THE INVENTION
[0007] The present invention provides combinations of antiviral
compounds, in particular compositions and methods for inhibition of
HIV. In an exemplary aspect, the invention includes a composition
including tenofovir disoproxil fumarate and emtricitabine which has
anti-HIV activity. The composition of tenofovir DF and
emtricitabine is both chemically stable and either synergistic
and/or reduces the side effects of one or both of tenofovir DF and
emtricitabine. Increased patient compliance is likely in view of
the lower pill burden and simplified dosing schedule.
[0008] The present invention relates to therapeutic combinations of
[2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid
diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil
fumarate, tenofovir DF, TDF, Viread.RTM.) and
(2R,5S,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-
-pyrimidin-2-one (emtricitabine, Emtriva.TM., (-)-cis FTC) and
their use in the treatment of HIV infections including infections
with HIV mutants bearing resistance to nucleoside and/or
non-nucleoside inhibitors. The present invention is also concerned
with pharmaceutical compositions and formulations of said
combinations of tenofovir disoproxil fumarate and emtricitabine.
Another aspect of the invention is a pharmaceutical formulation
comprising a physiologically functional derivative of tenofovir
disoproxil fumarate or a physiologically functional derivative of
emtricitabine.
[0009] Therapeutic combinations and pharmaceutical compositions and
formulations of the invention include the combination of PMAE or
PMPA (tenofovir) compounds with emtricitabine or
(2R,5S,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidi-
n-2-one (3TC, lamivudine, Epivir.TM.), and their use in the
treatment of HIV infections.
[0010] One aspect of the invention is a method for the treatment or
prevention of the symptoms or effects of an HIV infection in an
infected animal which comprises administering to, i.e. treating,
said animal with a therapeutically effective amount of a
combination comprising
[2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid
diisopropoxycarbonyloxymethyl ester fumarate (tenofovir DF, DIP) or
a physiologically functional derivative thereof, and
(2R,5S,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-
-pyrimidin-2-one (emtricitabine) or a physiologically functional
derivative thereof.
[0011] Another aspect of the invention is a unit dosage form of a
therapeutic combination comprising tenofovir disoproxil fumarate
and emtricitabine, or physiological functional derivatives thereof.
The unit dosage form may be formulated for administration by oral
or other routes and is unexpectedly chemically stable in view of
the properties of the structurally diverse components.
[0012] Another aspect of the invention is directed to chemically
stable combination antiviral compositions comprising tenofovir
disoproxil fumarate and emtricitabine. In a further aspect of the
invention, the chemically stable combinations of tenofovir
disoproxil fumarate and emtricitabine further comprise a third
antiviral agent. In this three-component mixture, the unique
chemical stability of tenofovir disoproxil fumarate and
emtricitabine is taken advantage of in order to enable the
combination with the third antiviral agent. Particularly useful
third agents include, by way of example and not limitation, those
of Table A. Preferably, the third component is an agent approved
for antiviral use in humans, more preferably, it is an NNRTI or a
protease inhibitor (PI), more preferably yet, it is an NNRTI. In a
particularly preferred embodiment, the invention is directed to a
combination of the chemically stable mixture of tenofovir
disoproxil fumarate and emtricitabine together with efavirenz.
[0013] Another aspect of the invention is a patient pack comprising
at least one, typically two, and optionally, three active
ingredients and other antiviral agents selected from tenofovir
disoproxil fumarate and emtricitabine, and an information insert
containing directions on the use of tenofovir disoproxil fumarate
and emtricitabine together in combination.
[0014] Another aspect of the invention is a process for preparing
the combinations hereinbefore described, which comprises bringing
into association tenofovir DF and emtricitabine of the combination
in a medicament to provide an antiviral effect. In a further aspect
of the present invention, there is provided the use of a
combination of the present invention in the manufacture of a
medicament for the treatment of any of the aforementioned viral
infections or conditions.
DETAILED DESCRIPTION OF THE INVENTION
[0015] While the invention will be described in conjunction with
the enumerated claims, it will be understood that they are not
intended to limit the invention to those claims. On the contrary,
the invention is intended to cover all alternatives, modifications,
and equivalents, which may be included within the scope of the
present invention as defined by the claims.
Definitions
[0016] Unless stated otherwise, the following terms and phrases as
used herein are intended to have the following meanings:
[0017] When tradenames are used herein, applicants intend to
independently include the tradename product and the active
pharmaceutical ingredient(s) of the tradename product.
[0018] The term "chemical stability" means that the two primary
antiviral agents in combination are substantially stable to
chemical degradation. Preferably, they are sufficiently stable in
physical combination to permit commercially useful shelf life of
the combination product. Typically, "chemically stable" means that
a first component of the mixture does not act to degrade a second
component when the two are brought into physical combination to
form a pharmaceutical dosage form. More typically, "chemically
stable" means that the acidity of a first component does not
catalyzes or otherwise accelerate the acid decomposition of a
second component. By way of example and not limitation, in one
aspect of the invention, "chemically stable" means that tenofovir
disoproxil fumarate is not substantially degraded by the acidity of
emtricitabine. "Substantially" in this context means at least about
less than 10%, preferably less than 1%, more preferably less than
0.1%, more preferably yet, less than 0.01% acid degradation of
tenofovir disoproxil fumarate over a 24-hour period when the
products are in a pharmaceutical dosage form.
[0019] The terms "synergy" and "synergistic" mean that the effect
achieved with the compounds used together is greater than the sum
of the effects that results from using the compounds separately,
i.e. greater than what would be predicted based on the two active
ingredients administered separately. A synergistic effect may be
attained when the compounds are: (1) co-formulated and administered
or delivered simultaneously in a combined formulation; (2)
delivered by alternation or in parallel as separate formulations;
or (3) by some other regimen. When delivered in alternation
therapy, a synergistic effect may be attained when the compounds
are administered or delivered sequentially, e.g. in separate
tablets, pills or capsules, or by different injections in separate
syringes. In general, during alternation therapy, an effective
dosage of each active ingredient is administered sequentially, i.e.
serially, whereas in combination therapy, effective dosages of two
or more active ingredients are administered together. A synergistic
antiviral effect denotes an antiviral effect which is greater than
the predicted purely additive effects of the individual compounds
of the combination.
[0020] The term "physiologically functional derivative" means a
pharmaceutically active compound with equivalent or near equivalent
physiological functionality to tenofovir DF or emtricitabine when
administered in combination with another pharmaceutically active
compound in a combination of the invention. As used herein, the
term "physiologically functional derivative" includes any:
physiologically acceptable salt, ether, ester, prodrug, solvate,
stereoisomer including enantiomer, diastereomer or
stereoisomerically enriched or racemic mixture, and any other
compound which upon administration to the recipient, is capable of
providing (directly or indirectly) such a compound or an
antivirally active metabolite or residue thereof.
[0021] "Bioavailability" is the degree to which the
pharmaceutically active agent becomes available to the target
tissue after the agent's introduction into the body. Enhancement of
the bioavailability of a pharmaceutically active agent can provide
a more efficient and effective treatment for patients because, for
a given dose, more of the pharmaceutically active agent will be
available at the targeted tissue sites.
[0022] The compounds of the combinations of the invention may be
referred to as "active ingredients" or "pharmaceutically active
agents."
[0023] The term "prodrug" as used herein refers to any compound
that when administered to a biological system generates the drug
substance, i.e. active ingredient, as a result of spontaneous
chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or
metabolic chemical reaction(s).
[0024] "Prodrug moiety" means a labile functional group which
separates from the active inhibitory compound during metabolism,
systemically, inside a cell, by hydrolysis, enzymatic cleavage, or
by some other process (Bundgaard, Hans, "Design and Application of
Prodrugs" in Textbook of Drug Design and Development (1991), P.
Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic
Publishers, pp. 113-191). Prodrug moieties can serve to enhance
solubility, absorption and lipophilicity to optimize drug delivery,
bioavailability and efficacy. A "prodrug" is thus a covalently
modified analog of a therapeutically-active compound.
[0025] "Alkyl" means a saturated or unsaturated, branched,
straight-chain, branched, or cyclic hydrocarbon radical derived by
the removal of one hydrogen atom from a single carbon atom of a
parent alkane, alkene, or alkyne. Typical alkyl groups consist of
1-18 saturated and/or unsaturated carbons, such as normal,
secondary, tertiary or cyclic carbon atoms. Examples include, but
are not limited to: methyl, Me(-CH.sub.3), ethyl,
Et(-CH.sub.2CH.sub.3), acetylenic (--C.ident.CH), ethylene, vinyl
(--CH.dbd.CH.sub.2), 1-propyl, n-Pr, n-propyl
(--CH.sub.2CH.sub.2CH.sub.3), 2-propyl, i-Pr, i-propyl
(--CH(CH.sub.3).sub.2), allyl (--CH.sub.2CH.dbd.CH.sub.2),
propargyl (--CH.sub.2C.dbd.CH), cyclopropyl (--C.sub.3H.sub.5),
1-butyl, n-Bu, n-butyl (--CH.sub.2CH.sub.2CH.sub.2CH.sub.3),
2-methyl-1-propyl, i-Bu, i-butyl (--CH.sub.2CH(CH.sub.3).sub.2),
2-butyl, s-Bu, s-butyl (--CH(CH.sub.3)CH.sub.2CH.sub.3),
2-methyl-2-propyl, t-Bu, t-butyl (--C(CH.sub.3).sub.3), 1-pentyl,
n-pentyl, (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), cyclopentyl
(--C.sub.5H.sub.9), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 5-hexenyl
(--CH.sub.2 CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH.sub.2) 1-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)), cyclohexyl
(--C.sub.6H.sub.11), 2-methyl-2-pentyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3), 3-methyl-2-pentyl
(--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3), 4-methyl-2-pentyl
(--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2), 3-methyl-3-pentyl
(--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2), 2-methyl-3-pentyl
(--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2), 2,3-dimethyl-2-butyl
(--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2), and 3,3-dimethyl-2-butyl
(--CH(CH.sub.3)C(CH.sub.3).sub.3.
[0026] "Aryl" means a monovalent aromatic hydrocarbon radical of
6-20 carbon atoms derived by the removal of one hydrogen atom from
a single carbon atom of a parent aromatic ring system. Typical aryl
groups include, but are not limited to, radicals derived from
benzene, substituted benzene, naphthalene, anthracene, biphenyl,
and the like.
[0027] "Arylalkyl" refers to an acyclic alkyl radical in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal
or sp.sup.3 carbon atom, is replaced with an aryl radical. Typical
arylalkyl groups include, but are not limited to, benzyl,
2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,
2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,
2-naphthophenylethan-1-yl and the like. The arylalkyl group 6 to 20
carbon atoms e.g., the alkyl moiety, including alkanyl, alkenyl or
alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and
the aryl moiety is 5 to 14 carbon atoms.
[0028] "Substituted alkyl", "substituted aryl", and "substituted
arylalkyl" mean alkyl, aryl, and arylalkyl respectively, in which
one or more hydrogen atoms are each independently replaced with a
substituent. Typical substituents include, but are not limited to,
--X, --R, --O.sup.-, --OR, --SR, --S.sup.-, --NR.sub.2, --NR.sub.3,
.dbd.NR, --CX.sub.3, --CN, --OCN, --SCN, --N.dbd.C.dbd.O, --NCS,
--NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3, NC(.dbd.O)R,
--C(.dbd.O)R, --C(.dbd.O)NRR--S(.dbd.O).sub.2O.sup.-,
--S(.dbd.O).sub.2OH, --S(.dbd.O).sub.2R, --OS(.dbd.O).sub.2OR,
--S(.dbd.O).sub.2NR, --S(.dbd.O)R, --OP(.dbd.O)O.sub.2RR,
--P(.dbd.O)O.sub.2RR--P(.dbd.O)(O.sup.-).sub.2,
--P(.dbd.O)(OH).sub.2, --C(.dbd.O)R, --C(.dbd.O)X, --C(S)R,
--C(O)OR, --C(O)O.sup.-, --C(S)OR, --C(O)SR, --C(S)SR, --C(O)NRR,
--C(S)NRR, --C(NR)NRR, where each X is independently a halogen: F,
Cl, Br, or I; and each R is independently --H, alkyl, aryl,
heterocycle, or prodrug moiety.
[0029] "Heteroaryl" and "Heterocycle" refer to a ring system in
which one or more ring atoms is a heteroatom, e.g. nitrogen,
oxygen, and sulfur. Heterocycles are described in: Katritzky, Alan
R., Rees, C. W., and Scriven, E. Comprehensive Heterocyclic
Chemistry (1996) Pergamon Press; Paquette, Leo A.; Principles of
Modern Heterocyclic Chemistry W. A. Benjamin, New York, (1968),
particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of
Heterocyclic Compounds, A series of Monographs" (John Wiley &
Sons, New York, 1950 to present), in particular Volumes 13, 14, 16,
19, and 28. Exemplary heterocycles include but are not limited to
substituents, i.e. radicals, derived from pyrrole, indole, furan,
benzofuran, thiophene, benzothiophene, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-imidazole,
4-imidazole, 3-pyrazole, 4-pyrazole, pyridazine, pyrimidine,
pyrazine, purine, cinnoline, pthalazine, quinazoline, quinoxaline,
3-(1,2,4-N)-triazolyl, 5-(1,2,4-N)-triazolyl, 5-tetrazolyl,
4-(1-O,3-N)-oxazole, 5-(1-O,3-N)-oxazole, 4-(1-S,3-N)-thiazole,
5-(1-S,3-N)-thiazole, 2-benzoxazole, 2-benzothiazole,
4-(1,2,3-N)-benzotriazole, and benzimidazole.
[0030] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., Stereochemistrv of Organic Compounds
(1994) John Wiley & Sons, Inc., New York. Many organic
compounds exist in optically active forms, i.e., they have the
ability to rotate the plane of plane-polarized light. In describing
an optically active compound, the prefixes D and L or R and S are
used to denote the absolute configuration of the molecule about its
chiral center(s). The prefixes d and L or (+) and (-) are employed
to designate the sign of rotation of plane-polarized light by the
compound, with (-) or 1 meaning that the compound is levorotatory.
A compound prefixed with (+) or d is dextrorotatory. For a given
chemical structure, these compounds, called stereoisomers, are
identical except that they are mirror images of one another. A
specific stereoisomer is also referred to as an enantiomer, and a
mixture of such isomers is often called an enantiomeric mixture. A
50:50 mixture of enantiomers is referred to as a racemic mixture or
a racemate. The terms "racemic mixture" and "racemate" refer to an
equimolar mixture of two enantiomeric species, devoid of optical
activity.
[0031] The term "chiral" refers to molecules which have the
property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0032] The term "stereoisomers" refers to compounds which have
identical chemical constitution, but differ with regard to the
arrangement of the atoms or groups in space.
[0033] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties, e.g.
melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers may separate under high
resolution analytical procedures such as electrophoresis and
chromatography.
[0034] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
Active Ingredients of the Combinations
[0035] The present invention provides novel combinations of two or
more active ingredients being employed together. In some
embodiments, a synergistic antiviral effect is achieved. In other
embodiments, a chemically stable combination is obtained. The
combinations include at least one active ingredient selected from
(1) tenofovir disoproxil fumarate and physiologically functional
derivatives, and at least one active ingredient selected from (2)
emtricitabine and physiologically functional derivatives. The term
"synergistic antiviral effect" is used herein to denote an
antiviral effect which is greater than the predicted purely
additive effects of the individual components (a) and (b) of the
combination.
[0036] Tenofovir disoproxil fumarate (also known as Viread.RTM.,
Tenofovir DF, Tenofovir disoproxil, TDF, Bis-POC-PMPA (U.S. Pat.
Nos. 5,935,946, 5,922,695, 5,977,089, 6,043,230, 6,069,249) is a
prodrug of tenofovir, and has the structure: ##STR1##
[0037] and including fumarate salt
(HO.sub.2CCH.sub.2CH.sub.2CO.sub.2.sup.-).
[0038] The chemical names for Tenofovir disoproxil include:
[2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid
diisopropoxycarbonyloxymethyl ester;
9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl-
]adenine; and 2,4,6,8-tetraoxa-5-phosphanonanedioic acid,
5-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]-,
bis(1-methylethyl)ester, 5-oxide. The CAS Registry numbers include:
201341-05-1; 202138-50-9; 206184-49-8. It should be noted that the
ethoxymethyl unit of tenofovir has a chiral center. The R (rectus,
right handed configuration) enantiomer is shown. However, the
invention also includes the S isomer. The invention includes all
enantiomers, diastereomers, racemates, and enriched stereoisomer
mixtures of tenofovir (PMPA) and physiologically functional
derivatives thereof.
[0039] PMPA or tenofovir (U.S. Pat. Nos. 4,808,716, 5,733,788,
6,057,305) has the structure: ##STR2##
[0040] The chemical names of PMPA, tenofovir include:
(R)-9-(2-phosphonylmethoxypropyl)adenine; and phosphonic acid,
[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]. The CAS
Registry number is 147127-20-6.
[0041] Tenofovir disoproxil fumarate (DF) is a nucleotide reverse
transcriptase inhibitor approved in the United States in 2001 for
the treatment of HIV-1 infection in combination with other
antiretroviral agents. Tenofovir disoproxil fumarate or Viread.RTM.
(Gilead Science, Inc.) is the fumarate salt of tenofovir
disoproxil. Viread.RTM. may be named as:
9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]meth-
oxy]propyl]adenine fumarate (1:1); or
2,4,6,8-tetraoxa-5-phosphanonanedioic acid,
5-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]-,
bis(1-methylethyl)ester, 5-oxide, (2E)-2-butenedioate (1:1). The
CAS Registry number is 202138-50-9.
[0042] Physiologically functional derivatives of tenofovir
disoproxil fumarate include PMEA (adefovir,
9-((R)-2-(phosphonomethoxy)ethyl)adenine) and PMPA compounds.
Exemplary combinations include a PMEA or PMPA compound in
combination with emtricitabine or 3TC. PMEA and PMPA compounds have
the structures: ##STR3## where PMEA (R.sup.3 is H) and PMPA (R3 is
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted alkyl, or
CH.sub.2OR.sup.8 where R.sup.8 is C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 hydroxyalkyl or C.sub.1-C.sub.6 haloalkyl. R.sup.6
and R.sup.7 are independently H or C.sub.1-C.sub.6 alkyl. R.sup.4
and R.sup.5 are independently H, NH.sub.2, NHR or NR.sub.2 where R
is C.sub.1-C.sub.6 alkyl. R.sup.1 and R.sup.2 are independently H,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted alkyl,
C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted aryl,
C.sub.6-C.sub.20 arylalkyl, C.sub.6-C.sub.20 substituted arylalkyl,
acyloxymethyl esters --CH.sub.2C(.dbd.O)R.sup.9 (e.g. POM) or
acyloxymethyl carbonates --CH.sub.2C(.dbd.O)OR.sup.9 (e.g. POC)
where R.sup.9 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted
alkyl, C.sub.6-C.sub.20 aryl or C.sub.6-C.sub.20 substituted aryl.
For example, R.sub.1 and R.sub.2 may be pivaloyloxymethoxy, POM,
--CH.sub.2C(.dbd.O)C(CH.sub.3).sub.3;
--CH.sub.2C(.dbd.O)OC(CH.sub.3).sub.3; or POC,
--CH.sub.2C(.dbd.O)OCH(CH.sub.3).sub.2. Also for example, tenofovir
has the structure where R.sup.3 is CH.sub.3, and R.sup.1, R.sup.2,
R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are H. Dialkyl phosphonates
may be prepared according to the methods of: Quast et al (1974)
Synthesis 490; Stowell et al (1990) Tetrahedron Lett. 3261; U.S.
Pat. No. 5,663,159.
[0043] The PMPA compound may be enantiomerically-enriched or
purified (single stereoisomer) where the carbon atom bearing
R.sup.3 may be the R or S enantiomer. The PMPA compound may be a
racemate, i.e. a mixture of R and S stereoisomers.
[0044] Adefovir (9-(2-phosphonomethoxyethyl)adenine where
R.sub.1-R.sub.7.dbd.H) is an exemplary PMEA compound (U.S. Pat.
Nos. 4,808,716, 4,724,233). As the bis-pivalate prodrug, Adefovir
dipivoxil, also known as bis-POM PMEA, (R.sub.3-R.sub.7.dbd.H,
R.sub.1 and R.sub.2=--CH.sub.2C(.dbd.O)C(CH.sub.3).sub.3, pivoxil,
POM, pivaloyloxymethoxy), is effective against HIV and Hepatitis B
infections (U.S. Pat. Nos. 5,663,159, 6,451,340). Adefovir
dipivoxil has demonstrated minor to moderate synergistic inhibition
of HIV replication in combination with other compounds with
anti-HIV activity including PMPA, d4T, ddC, nelfinavir, ritonavir,
and saquinavir (Mulato et al (1997) Antiviral Research
36:91-97).
[0045] The invention includes all enantiomers, diastereomers,
racemates, and enriched stereoisomer mixtures of PMEA and PMPA, and
physiologically functional derivatives thereof.
[0046] Emtricitabine ((-)-cis-FIC, Emtriva.TM.), a single
enantiomer of FTC, is a potent nucleoside reverse transcriptase
inhibitor approved for the treatment of HIV (U.S. Pat. Nos.
5,047,407, 5,179,104, 5,204,466, 5,210,085, 5,486,520, 5,538,975,
5,587,480, 5,618,820, 5,763,606, 5,814,639, 5,914,331, 6,114,343,
6,180,639, 6,215,004; WO 02/070518). The single enantiomer
emtricitabine has the structure: ##STR4##
[0047] The chemical names for emtricitabine include: (-)-cis-FIC;
.beta.-L-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane;
(2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine;
and
4-amino-5-fluoro-1-(2-hydroxymethyl-[1,3]-(2R,5S)-oxathiolan-5-yl)-1H-pyr-
imidin-2-one. The CAS Registry numbers include: 143491-57-0;
143491-54-7. It should be noted that FTC contains two chiral
centers, at the 2 and 5 positions of the oxathiolane ring, and
therefore can exist in the form of two pairs of optical isomers
(i.e. enantiomers) and mixtures thereof including racemic mixtures.
Thus, FTC may be either a cis or a trans isomer or mixtures
thereof. Mixtures of cis and trans isomers are diastereomers with
different physical properties. Each cis and trans isomer can exist
as one of two enantiomers or mixtures thereof including racemic
mixtures. The invention includes all enantiomers, diastereomers,
racemates, and enriched stereoisomer mixtures of emtricitabine and
physiologically functional derivatives thereof. For example, the
invention includes physiological functional derivatives such as the
1:1 racemic mixture of the enantiomers
(2R,5S,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-
-pyrimidin-2-one (emtricitabine) and its mirror image (2S,5R,
cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimi-
din-2-one, or mixtures of the two enantiomers in any relative
amount. The invention also includes mixtures of cis and trans forms
of FTC.
[0048] Physiologically functional derivatives of emtricitabine
include 1,3 oxathiolane nucleosides having the structure:
##STR5##
[0049] In the 1,3 oxathiolane nucleoside structure above, B is a
nucleobase including any nitrogen-containing heterocyclic moiety
capable of forming Watson-Crick hydrogen bonds in pairing with a
complementary nucleobase or nucleobase analog, e.g. a purine, a
7-deazapurine, or a pyrimidine. Examples of B include the naturally
occurring nucleobases: adenine, guanine, cytosine, uracil, thymine,
and minor constituents and analogs of the naturally occurring
nucleobases, e.g. 7-deazaadenine, 7-deazaguanine,
7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine,
nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine,
2,6-diaminopurine, hypoxanthine, pseudouridine, 5-fluorocytosine,
5-chlorocytosine, 5-bromocytosine, 5-iodocytosine, pseudocytosine,
pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine,
7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine,
4-thiouracil, O.sup.6-methylguanine, N.sup.6-methyladenine,
O.sup.4-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil,
4-methylindole, pyrazolo[3,4-D]pyrimidines (U.S. Pat. Nos.
6,143,877 and 6,127,121; WO 01/38584), and ethenoadenine (Fasman
(1989) in Practical Handbook of Biochemistry and Molecular Biology,
pp. 385-394, CRC Press, Boca Raton, Fla.).
[0050] Nucleobases B may be attached in the configurations of
naturally-occurring nucleic acids to the 1,3 oxathiolane moiety
through a covalent bond between the N-9 of purines, e.g.
adenin-9-yl and guanin-9-yl, or N-1 of pyrimidines, e.g.
thymin-1-yl and cytosin-1-yl (Blackburn, G. and Gait, M. Eds. "DNA
and RNA structure" in Nucleic Acids in Chemistry and Biology,
2.sup.nd Edition, (1996) Oxford University Press, pp. 15-81).
[0051] Also in the 1,3 oxathiolane nucleoside structure above, R is
H, C.sub.1-C.sub.18 alkyl, C.sub.1-C.sub.18 substituted alkyl,
C.sub.2-C.sub.18 alkenyl, C.sub.2-C.sub.18 substituted alkenyl,
C.sub.2-C.sub.18 alkynyl, C.sub.2-C.sub.18 substituted alkynyl,
C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted aryl,
C.sub.2-C.sub.20 heterocycle, C.sub.2-C.sub.20 substituted
heterocycle, phosphonate, phosphophosphonate, diphosphophosphonate,
phosphate, diphosphate, triphosphate, polyethyleneoxy, or a prodrug
moiety.
[0052] Physiologically functional derivatives of emtricitabine also
include 3TC (lamivudine, Epivir.RTM.), a reverse transcriptase
inhibitor approved in the United States for the treatment of HIV-1
infection in combination with AZT as Combivir.RTM.
(GlaxoSmithKline). U.S. Pat. Nos. 5,859,021; 5,905,082; 6,177,435;
5,627,186; 6,417,191. Lamivudine (U.S. Pat. Nos. 5,587,480,
5,696,254, 5,618,820, 5,756,706, 5,744,596, 568,164, 5,466,806,
5,151,426) has the structure: ##STR6##
[0053] For example and for some therapeutic uses, 3TC may be a
physiologically functional derivative of emtricitabine in
combination with tenofovir DF or a physiologically functional
derivative of tenofovir DF.
[0054] It will be appreciated that tenofovir DF and emtricitabine,
and their physiologically functional derivatives may exist in keto
or enol tautomeric forms and the use of any tautomeric form thereof
is within the scope of this invention. Tenofovir DF and
emtricitabine will normally be utilized in the combinations of the
invention substantially free of the corresponding enantiomer, that
is to say no more than about 5% w/w of the corresponding enantiomer
will be present.
Prodrugs
[0055] The invention includes all prodrugs of tenofovir and
emtricitabine. An exemplary prodrug of tenofovir is tenofovir
disoproxil fumarate (TDF, Viread.RTM.). A large number of
structurally-diverse prodrugs have been described for phosphonic
acids (Freeman and Ross in Progress in Medicinal Chemistry 34:
112-147 (1997). A commonly used prodrug class is the acyloxyalkyl
ester, which was first used as a prodrug strategy for carboxylic
acids and then applied to phosphates and phosphonates by Farquhar
et al (1983) J. Pharm. Sci. 72: 324; also U.S. Pat. Nos. 4,816,570,
4,968,788, 5,663,159 and 5,792,756. Subsequently, the acyloxyalkyl
ester was used to deliver phosphonic acids across cell membranes
and to enhance oral bioavailability. A close variant of the
acyloxyalkyl ester strategy, the alkoxycarbonyloxyalkyl ester, may
also enhance oral bioavailability as a prodrug moiety in the
compounds of the combinations of the invention. Aryl esters of
phosphorus groups, especially phenyl esters, are reported to
enhance oral bioavailability (DeLambert et al (1994) J. Med. Chem.
37: 498). Phenyl esters containing a carboxylic ester ortho to the
phosphate have also been described (Khamnei and Torrence, (1996) J.
Med. Chem. 39:4109-4115). Benzyl esters are reported to generate
the parent phosphonic acid. In some cases, substituents at the
ortho- or para-position may accelerate the hydrolysis. Benzyl
analogs with an acylated phenol or an alkylated phenol may generate
the phenolic compound through the action of enzymes, e.g.
esterases, oxidases, etc., which in turn undergoes cleavage at the
benzylic C--O bond to generate the phosphoric acid and the quinone
methide intermediate. Examples of this class of prodrugs are
described by Mitchell et al (1992) J. Chem. Soc. Perkin Trans.
12345; Brook et al WO 91/19721. Still other benzylic prodrugs have
been described containing a carboxylic ester-containing group
attached to the benzylic methylene (Glazier et al WO 91/19721).
Thio-containing prodrugs are reported to be useful for the
intracellular delivery of phosphonate drugs. These proesters
contain an ethylthio group in which the thiol group is either
esterified with an acyl group or combined with another thiol group
to form a disulfide. Deesterification or reduction of the disulfide
generates the free thio intermediate which subsequently breaks down
to the phosphoric acid and episulfide (Puech et al (1993) Antiviral
Res., 22: 155-174; Benzaria et al (1996) J. Med. Chem. 39: 4958).
Cyclic phosphonate esters have also been described as prodrugs of
phosphorus-containing compounds.
[0056] Prodrug esters in accordance with the invention are
independently selected from the following groups: (1) mono-, di-,
and tri-phosphate esters of tenofovir or emtricitabine or any other
compound which upon administration to a human subject is capable of
providing (directly or indirectly) said mono-, di, or triphosphate
ester; (2) carboxylic acid esters (3) sulphonate esters, such as
alkyl- or aralkylsulphonyl (for example, methanesulphonyl); (4)
amino acid esters (for example, alanine, L-valyl or L-isoleucyl);
(5) phosphonate; and (6) phosphonamidate esters.
[0057] Ester groups (1)-(6) may be substituted with; straight or
branched chain C.sub.1-C.sub.18 alkyl (for example, methyl,
n-propyl, t-butyl, or n-butyl); C.sub.3-C.sub.12 cycloalkyl;
alkoxyalkyl (for example, methoxymethyl); arylalkyl (for example,
benzyl); aryloxyalkyl (for example, phenoxymethyl);
C.sub.5-C.sub.20 aryl (for example, phenyl optionally substituted
by, for example, halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, or amino; acyloxymethyl esters --CH.sub.2C(.dbd.O)R.sup.9
(e.g. POM) or acyloxymethyl carbonates --CH.sub.2C(.dbd.O)OR.sup.9
(e.g. POC) where R.sup.9 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
substituted alkyl, C.sub.6-C.sub.20 aryl or C.sub.6-C.sub.20
substituted aryl. For example, ester groups may be:
--CH.sub.2C(.dbd.O)C(CH.sub.3).sub.3,
--CH.sub.2C(.dbd.O)OC(CH.sub.3).sub.3 or
--CH.sub.2C(.dbd.O)OCH(CH.sub.3).sub.2.
[0058] An exemplary aryl moiety present in such esters comprises a
phenyl or substituted phenyl group. Many phosphate prodrug moieties
are described in U.S. Pat. No. 6,312,662; Jones et al (1995)
Antiviral Research 27:1-17; Kucera et al (1990) AIDS Res. Hum.
Retro Viruses 6:491-501; Piantadosi et al (1991) J. Med. Chem.
34:1408-14; Hosteller et al (1992) Antimicrob. Agents Chemother.
36:2025-29; Hostetler et al (1990) J. Biol. Chem. 265:611127; and
Siddiqui et al (1999) J. Med. Chem. 42:4122-28.
[0059] Pharmaceutically acceptable prodrugs refer to a compound
that is metabolized in the host, for example hydrolyzed or
oxidized, by either enzymatic action or by general acid or base
solvolysis, to form an active ingredient. Typical examples of
prodrugs of the active ingredients of the combinations of the
invention have biologically labile protecting groups on a
functional moiety of the active compound. Prodrugs include
compounds that can be oxidized, reduced, aminated, deaminated,
esterified, deesterified, alkylated, dealkylated, acylated,
deacylated, phosphorylated, dephosphorylated, or other functional
group change or conversion involving forming or breaking chemical
bonds on the prodrug.
Chemical Stability of a Pharmaceutical Formulation
[0060] The chemical stability of the active ingredients in a
pharmaceutical formulation is of concern to minimize the generation
of impurities and ensure adequate shelf-life. The active
ingredients, tenofovir disoproxil fumarate and emtricitabine, in
the pharmaceutical formulations of the invention have relatively
low pKa values, indicative of the potential to cause acidic
hydrolysis of the active ingredients. Emtricitabine, with a pKa of
2.65 (Emtriva.TM. Product Insert, Gilead Sciences, Inc. 2003,
available at gilead.com) is subject to hydrolytic deamination of
the 5-fluoro cytosine nucleobase to form the 5-fluoro uridine
nucleobase. Tenofovir disoproxil fumarate, with a pKa of 3.75 (Yuan
L. et al "Degradation Kinetics of Oxycarbonyloxymethyl Prodrugs of
Phosphonates in Solution", Pharmaceutical Research (2001) Vol. 18,
No. 2, 234-237), is subject also to hydrolytic deamination of the
exocyclic amine of the adenine nucleobase, and to hydrolysis of one
or both of the POC ester groups (U.S. Pat. No. 5,922,695). It is
desirable to formulate a therapeutic combination of tenofovir
disoproxil fumarate and emtricitabine, and the physiological
functional derivatives thereof, with a minimum of impurities and
adequate stability.
[0061] The combinations of the present invention provide
combination pharmaceutical dosage forms which are chemically stable
to acid degradation of: (1) a first component (such as tenofovir
disoproxil fumarate, and physiological functional derivatives; (2)
a second component (such as emtricitabine, and physiological
functional derivatives; and (3) optionally a third component having
antiviral activity. The third component includes anti-HIV agents
and include: protease inhibitors (PI), nucleoside reverse
transcriptase inhibitors (NRTI), non-nucleoside reverse
transcriptase inhibitors (NNRTI), and integrase inhibitors.
Exemplary third active ingredients to be administered in
combination with first and second components are shown in Table A.
First and second components are as defined in the above section
entitled: ACTIVE INGREDIENTS OF THE COMBINATIONS.
Salts
[0062] Any reference to any of the compounds in the compositions of
the invention also includes any physiologically acceptable salt
thereof. Examples of physiologically acceptable salts of tenofovir
DF, emtricitabine and their physiologically functional derivatives
include salts derived from an appropriate base, such as an alkali
metal (for example, sodium), an alkaline earth (for example,
magnesium), ammonium and NX.sub.4.sup.+ (wherein X is
C.sub.1-C.sub.4 alkyl), or an organic acid such as fumaric acid,
acetic acid, succinic acid. Physiologically acceptable salts of an
hydrogen atom or an amino group include salts of organic carboxylic
acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic,
malonic, malic, isethionic, lactobionic and succinic acids; organic
sulfonic acids, such as methanesulfonic, ethanesulfonic,
benzenesulfonic and p-toluenesulfonic acids; and inorganic acids,
such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
Physiologically acceptable salts of a compound of an hydroxy group
include the anion of said compound in combination with a suitable
cation such as Na.sup.+ and NX.sub.4.sup.+ (wherein X is
independently selected from H or a C.sub.1-C.sub.4 alkyl
group).
[0063] For therapeutic use, salts of active ingredients of the
combinations of the invention will be physiologically acceptable,
i.e. they will be salts derived from a physiologically acceptable
acid or base. However, salts of acids or bases which are not
physiologically acceptable may also find use, for example, in the
preparation or purification of a physiologically acceptable
compound. All salts, whether or not derived from a physiologically
acceptable acid or base, are within the scope of the present
invention.
Administration of the Formulations
[0064] While it is possible for the active ingredients of the
combination to be administered alone and separately as
monotherapies, it is preferable to administer them as a
pharmaceutical co-formulation. A two-part or three-part combination
may be administered simultaneously or sequentially. When
administered sequentially, the combination may be administered in
one, two, or three administrations.
[0065] Preferably, two-part or three-part combinations are
administered in a single pharmaceutical dosage form. More
preferably, a two-part combination is administered as a single oral
dosage form and a three-part combination is administered as two
identical oral dosage forms. Examples include a single tablet of
tenofovir disoproxil fumarate and emtricitabine, or two tablets of
tenofovir disoproxil fumarate, emtricitabine, and efavirenz.
[0066] It will be appreciated that the compounds of the combination
may be administered: (1) simultaneously by combination of the
compounds in a co-formulation or (2) by alternation, i.e.
delivering the compounds serially, sequentially, in parallel or
simultaneously in separate pharmaceutical formulations. In
alternation therapy, the delay in administering the second, and
optionally a third active ingredient, should not be such as to lose
the benefit of a synergistic therapeutic effect of the combination
of the active ingredients. By either method of administration (1)
or (2), ideally the combination should be administered to achieve
peak plasma concentrations of each of the active ingredients. A one
pill once-per-day regimen by administration of a combination
co-formulation may be feasible for some HIV-positive patients.
Effective peak plasma concentrations of the active ingredients of
the combination will be in the range of approximately 0.001 to 100
.mu.M. Optimal peak plasma concentrations may be achieved by a
formulation and dosing regimen prescribed for a particular patient.
It will also be understood that tenofovir DF and emtricitabine, or
the physiologically functional derivatives of either thereof,
whether presented simultaneously or sequentially, may be
administered individually, in multiples, or in any combination
thereof. In general, during alternation therapy (2), an effective
dosage of each compound is administered serially, where in
co-formulation therapy (1), effective dosages of two or more
compounds are administered together.
Formulation of the Combinations
[0067] When the individual components of the combination are
administered separately they are generally each presented as a
pharmaceutical formulation. The references hereinafter to
formulations refer unless otherwise stated to formulations
containing either the combination or a component compound thereof.
It will be understood that the administration of the combination of
the invention by means of a single patient pack, or patient packs
of each formulation, within a package insert diverting the patient
to the correct use of the invention is a desirable additional
feature of this invention. The invention also includes a double
pack comprising in association for separate administration,
formulations of tenofovir disoproxil fumarate and emtricitabine, or
a physiologically functional derivative of either or both
thereof.
[0068] The combination therapies of the invention include: (1) a
combination of tenofovir DF and emtricitabine or (2) a combination
containing a physiologically functional derivative of either or
both thereof.
[0069] The combination may be formulated in a unit dosage
formulation comprising a fixed amount of each active pharmaceutical
ingredient for a periodic, e.g. daily, dose or subdose of the
active ingredients.
[0070] Pharmaceutical formulations according to the present
invention comprise a combination according to the invention
together with one or more pharmaceutically acceptable carriers or
excipients and optionally other therapeutic agents. Pharmaceutical
formulations containing the active ingredient may be in any form
suitable for the intended method of administration. When used for
oral use for example, tablets, troches, lozenges, aqueous or oil
suspensions, dispersible powders or granules, emulsions, hard or
soft capsules, syrups or elixirs may be prepared (Remington's
Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.).
Compositions intended for oral use may be prepared according to any
method known to the art for the manufacture of pharmaceutical
compositions and such compositions may contain one or more agents
including antioxidants, sweetening agents, flavoring agents,
coloring agents and preserving agents, in order to provide a
palatable preparation. Tablets containing the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipient
which are suitable for manufacture of tablets are acceptable. These
excipients may be, for example, inert diluents, such as calcium or
sodium carbonate, lactose, lactose monohydrate, croscarmellose
sodium, povidone, calcium or sodium phosphate; granulating and
disintegrating agents, such as maize starch, or alginic acid;
binding agents, such as cellulose, microcrystalline cellulose,
starch, gelatin or acacia; and lubricating agents, such as
magnesium stearate, stearic acid or talc. Tablets may be uncoated
or may be coated by known techniques including microencapsulation
to delay disintegration and absorption in the gastrointestinal
tract and thereby provide a sustained action over a longer period.
For example, a time delay material such as glyceryl monostearate or
glyceryl distearate alone or with a wax may be employed.
[0071] Formulations for oral use may be also presented as hard
gelatin capsules where the active ingredient is mixed with an inert
solid diluent, for example pregelatinized starch, calcium phosphate
or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, such as peanut
oil, liquid paraffin or olive oil.
[0072] Aqueous suspensions of the invention contain the active
materials in admixture with excipients suitable for the manufacture
of aqueous suspensions. Such excipients include a suspending agent,
such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropyl methylcelluose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous
suspension may also contain one or more preservatives such as ethyl
or n-propyl p-hydroxybenzoate, one or more coloring agents, one or
more flavoring agents and one or more sweetening agents, such as
sucrose, sucralose or saccharin.
[0073] Oil suspensions may be formulated by suspending the active
ingredient in a vegetable oil, such as arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oral suspensions may contain a thickening agent, such
as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such
as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an antioxidant such as ascorbic acid,
BHT, etc.
[0074] Dispersible powders and granules of the invention suitable
for preparation of an aqueous suspension by the addition of water
provide the active ingredient in admixture with a dispersing or
wetting agent, a suspending agent, and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are
exemplified by those disclosed above. Additional excipients, for
example sweetening, flavoring and coloring agents, may also be
present.
[0075] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions or liposome formulations. The
oily phase may be a vegetable oil, such as olive oil or arachis
oil, a mineral oil, such as liquid paraffin, or a mixture of these.
Suitable emulsifying agents include naturally-occurring gums, such
as gum acacia and gum tragacanth, naturally occurring phosphatides,
such as soybean lecithin, esters or partial esters derived from
fatty acids and hexitol anhydrides, such as sorbitan monooleate,
and condensation products of these partial esters with ethylene
oxide, such as polyoxyethylene sorbitan monooleate. The emulsion
may also contain sweetening and flavoring agents. Syrups and
elixirs may be formulated with sweetening agents, such as glycerol,
sorbitol or sucrose. Such formulations may also contain a
demulcent, a preservative, a flavoring or a coloring agent.
[0076] The pharmaceutical compositions of the invention may be in
the form of a sterile injectable preparation, such as a sterile
injectable aqueous or oleaginous suspension. This suspension may be
formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents which have been
mentioned above. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent, such as a solution in
1,3-butane-diol or prepared as a lyophilized powder. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile fixed oils may conventionally be employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid may likewise be used in
the preparation of injectables.
[0077] The pharmaceutical compositions of the invention may be
injected parenterally, for example, intravenously,
intraperitoneally, intrathecally, intraventricularly,
intrastemally, intracranially, intramuscularly or subcutaneously,
or they may be administered by infusion techniques. They are best
used in the form of a sterile aqueous solution which may contain
other substances, for example, enough salts or glucose to make the
solution isotonic with blood. The aqueous solutions should be
suitably buffered (preferably to a pH of from 3 to 9), if
necessary. The preparation of suitable parenteral formulations
under sterile conditions is readily accomplished by standard
pharmaceutical techniques well known to those skilled in the
art.
[0078] The pharmaceutical compositions of the invention may also be
administered intranasally or by inhalation and are conveniently
delivered in the form of a dry powder inhaler or an aerosol spray
presentation from a pressurized container or a nebuliser with the
use of a suitable propellant, e.g. dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, a
hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFC 134a),
carbon dioxide or other suitable gas. In the case of a pressurized
aerosol, the dosage unit may be determined by providing a valve to
deliver a metered amount. The pressurized container or nebuliser
may contain a solution or suspension of the composition, e.g. using
a mixture of ethanol and the propellant as the solvent, which may
additional contain a lubricant, e.g. sorbitan trioleate. Capsules
and cartridges (made, for example, from gelatin) for use in an
inhaler or insufflator may be formulated to contain a powder mix of
a compound of the formula (I) and a suitable powder base such as
lactose or starch. Aerosol or dry powder formulations are
preferably arranged so that each metered dose or "puff" contains
from 20 .mu.g to 20 mg of a composition for delivery to the
patient. The overall daily dose with an aerosol will be in the
range of from 20 .mu.g to 20 mg which may be administered in a
single dose or, more usually, in divided doses throughout the
day.
[0079] The amount of active ingredient that may be combined with
the carrier material to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans may contain approximately 1 to
1000 mg of active material compounded with an appropriate and
convenient amount of carrier material which may vary from about 5
to about 95% of the total compositions (weight:weight). The
pharmaceutical composition can be prepared to provide easily
measurable amounts for administration. For example, an aqueous
solution intended for intravenous infusion may contain from about 3
to 500 .mu.g of the active ingredient per milliliter of solution in
order that infusion of a suitable volume at a rate of about 30
mL/hr can occur. As noted above, formulations of the present
invention suitable for oral administration may be presented as
discrete units such as capsules, cachets or tablets each containing
a predetermined amount of the active ingredient; as a powder or
granules; as a solution or a suspension in an aqueous or
non-aqueous liquid; or as an oil-in-water liquid emulsion or a
water-in-oil liquid emulsion. The active ingredient may also be
administered as a bolus, electuary or paste.
[0080] The combinations of the invention may conveniently be
presented as a pharmaceutical formulation in a unitary dosage form.
A convenient unitary dosage formulation contains the active
ingredients in any amount from 1 mg to 1 g each, for example but
not limited to, 10 mg to 300 mg. The synergistic effects of
tenofovir DF in combination with emtricitabine may be realized over
a wide ratio, for example 1:50 to 50:1 (tenofovir
DF:emtricitabine). In one embodiment, the ratio may range from
about 1:10 to 10:1. In another embodiment, the weight/weight ratio
of tenofovir to emtricitabine in a co-formulated combination dosage
form, such as a pill, tablet, caplet or capsule will be about 1,
i.e. an approximately equal amount of tenofovir DP and
emtricitabine. In other exemplary co-formulations, there may be
more or less tenofovir than FTC. For example, 300 mg tenofovir DF
and 200 mg emtricitabine can be co-formulated in a ratio of 1.5:1
(tenofovir DF: emtricitabine). In one embodiment, each compound
will be employed in the combination in an amount at which it
exhibits antiviral activity when used alone. Exemplary Formulations
A, B, C, D, E, and F (Examples) have ratios of 12:1 to 1:1
(tenofovir DF: emtricitabine). Exemplary Formulations A, B, C, D,
E, and F use amounts of tenofovir DF and emtricitabine ranging from
25 mg to 300 mg. Other ratios and amounts of the compounds of said
combinations are contemplated within the scope of the
invention.
[0081] A unitary dosage form may further comprise tenofovir DF and
emtricitabine, or physiologically functional derivatives of either
thereof, and a pharmaceutically acceptable carrier.
[0082] It will be appreciated by those skilled in the art that the
amount of active ingredients in the combinations of the invention
required for use in treatment will vary according to a variety of
factors, including the nature of the condition being treated and
the age and condition of the patient, and will ultimately be at the
discretion of the attending physician or health care practitioner.
The factors to be considered include the route of administration
and nature of the formulation, the animal's body weight, age and
general condition and the nature and severity of the disease to be
treated. For example, in a Phase I/II monotherapy study of
emtricitabine, patients received doses ranging from 25 mg to 200 mg
twice-a-day for two weeks. At each dose regimen greater or equal to
200 mg, a 98-percent (1.75 Iog10) or greater viral suppression was
observed. A once-a-day dose of 200 mg of emtricitabine reduced the
viral load by an average of 99 percent (1.92 Iog10). Viread.RTM.
(tenofovir DF) has been approved by the FDA for the treatment and
prophylaxis of HIV infection as a 300 mg oral tablet. Emtriva.TM.
(emtricitabine) has been approved by the FDA for the treatment of
HIV as a 200 mg oral tablet.
[0083] It is also possible to combine any two of the active
ingredients in a unitary dosage form for simultaneous or sequential
administration with a third active ingredient. The three-part
combination may be administered simultaneously or sequentially.
When administered sequentially, the combination may be administered
in two or three administrations. Third active ingredients have
anti-HIV activity and include protease inhibitors (PI), nucleoside
reverse transcriptase inhibitors (NRTI), non-nucleoside reverse
transcriptase inhibitors (NNRTI), and integrase inhibitors.
Exemplary third active ingredients to be administered in
combination with tenofovir DF, emtricitabine, and their
physiological functional derivatives, are shown in Table A.
TABLE-US-00001 TABLE A 5,6 dihydro-5-azacytidine 5-aza
2'deoxycytidine 5-azacytidine 5-yl-carbocyclic 2'-deoxyguanosine
(BMS200,475) 9 (arabinofuranosyl)guanine; 9-(2'
deoxyribofuranosyl)guanine 9-(2'-deoxy
2'fluororibofuranosyl)-2,6-diaminopurine 9-(2'-deoxy
2'fluororibofuranosyl)guanine 9-(2'-deoxyribofuranosyl)-2,6
diaminopurine 9-(arabinofuranosyl)-2,6 diaminopurine Abacavir,
Ziagen .RTM. Acyclovir, ACV; 9-(2-hydroxyethoxylmethyl)guanine
Adefovir dipivoxil, Hepsera .RTM. amdoxivir, DAPD Amprenavir,
Agenerase .RTM. araA; 9-.beta.-D-arabinofuranosyladenine
(Vidarabine) atazanivir sulfate (Reyataz .RTM.) AZT;
3'-azido-2',3'-dideoxythymdine, Zidovudine, (Retrovir .RTM.) BHCG;
(.+-.)-(1a,2b,3a)-9-[2,3- bis(hydroxymethyl)cyclobutyl]guanine
BMS200,475; 5-yl-carbocyclic 2'-deoxyguanosine Buciclovir; (R)
9-(3,4-dihydroxybutyl)guanine BvaraU;
1-.beta.-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (Sorivudine)
Calanolide A Capravirine CDG; carbocyclic 2'-deoxyguanosine
Cidofovir, HPMPC; (S)-9-(3-hydroxy-2-
phosphonylmethoxypropyl)cytosine Clevudine, L-FMAU;
2'-Fluoro-5-methyl-.beta.-L-arabino- furanosyluracil Combivir .RTM.
(lamivudine/zidovudine) Cytallene;
[1-(4'-hydroxy-1',2'-butadienyl)cytosine] d4C;
3'-deoxy-2',3'-didehydrocytidine DAPD;
(-)-.beta.-D-2,6-diaminopurine dioxolane ddA;
2',3'-dideoxyadenosine ddAPR;
2,6-diaminopurine-2',3'-dideoxyriboside ddC; 2',3'-dideoxycytidine
(Zalcitabine) ddI; 2',3'-dideoxyinosine, didanosine, (Videx .RTM.,
Videx .RTM. EC) Delavirdine, Rescriptor .RTM. Didanosine, ddI,
Videx .RTM.; 2',3'-dideoxyinosine DXG; dioxolane guanosine
E-5-(2-bromovinyl)-2'-deoxyuridine Efavirenz, Sustiva .RTM.
Enfuvirtide, Fuzeon .RTM. F-ara-A; fluoroarabinosyladenosine
(Fludarabine) FDOC;
(-)-.beta.-D-5-fluoro-1-[2-(hydroxymethyl)-1,3-dioxolane]cytosine
FEAU; 2'-deoxy-2'-fluoro-1-.beta.-D-arabinofuranosyl-5-ethyluracil
FIAC; 1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5-iodocytosine
FIAU; 1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5-iodouridine
FLG; 2',3'-dideoxy-3'-fluoroguanosine FLT;
3'-deoxy-3'-fluorothymidine Fludarabine; F-ara-A;
fluoroarabinosyladenosine FMAU;
2'-Fluoro-5-methyl-.beta.-L-arabino-furanosyluracil FMdC Foscarnet;
phosphonoformic acid, PFA FPMPA;
9-(3-fluoro-2-phosphonylmethoxypropyl)adenine Gancyclovir, GCV;
9-(1,3-dihydroxy-2-propoxymethyl)guanine GS-7340;
9-[R-2-[[(S)--[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-
phenoxyphosphinyl]methoxy]propyl]adenine HPMPA;
(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine HPMPC;
(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (Cidofovir)
Hydroxyurea, Droxia .RTM. Indinavir, Crixivan .RTM. Kaletra .RTM.
(lopinavir/ritonavir) Lamivudine, 3TC, Epivir .TM.; (2R,5S,
cis)-4-amino-1-(2-hydroxymethyl-
1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one L-d4C;
L-3'-deoxy-2',3'-didehydrocytidine L-ddC; L-2',3'-dideoxycytidine
L-Fd4C; L-3'-deoxy-2',3'-didehydro-5-fluorocytidine L-FddC;
L-2',3'-dideoxy-5-fluorocytidine Lopinavir Nelfinavir, Viracept
.RTM. Nevirapine, Viramune .RTM. Oxetanocin A;
9-(2-deoxy-2-hydroxymethyl-.beta.-D-erythro- oxetanosyl)adenine
Oxetanocin G; 9-(2-deoxy-2-hydroxymethyl-.beta.-D-erythro-
oxetanosyl)guanine Penciclovir PMEDAP;
9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine PMPA, tenofovir;
(R)-9-(2-phosphonylmethoxypropyl)adenine PPA; phosphonoacetic acid
Ribavirin; 1-.beta.-D-ribofuranosyl-1,2,4-triazole-3-carboxamide
Ritonavir, Norvir .RTM. Saquinavir, Invirase .RTM., Fortovase .RTM.
Sorivudine, BvaraU;
1-.beta.-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil Stavudine,
d4T, Zerit .RTM.; 2',3'-didehydro-3'-deoxythymidine
Trifluorothymidine, TFT; Trifluorothymidine Trizivir .RTM.
(abacavir sulfate/lamivudine/zidovudine) Vidarabine, araA;
9-.beta.-D-arabinofuranosyladenine Zalcitabine, Hivid .RTM., ddC;
2',3'-dideoxycytidine Zidovudine, AZT, Retrovir .RTM.;
3'-azido-2',3'-dideoxythymdine Zonavir;
5-propynyl-1-arabinosyluracil
[0084] Another aspect of the present invention is a three-part
combination comprising tenofovir DF, FIC, and
9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]-
methoxy]propyl]adenine, also designated herein as GS-7340, which
has the structure: ##STR7##
[0085] GS-7340 is a prodrug of tenofovir and the subject of
commonly owned, pending application, U.S. Ser. No. 09/909,560,
filed Jul. 20, 2001 and Becker et al WO 02/08241.
[0086] For example, a ternary unitary dosage may contain 1 mg to
1000 mg of tenofovir disoproxil fumarate, 1 mg to 1000 mg of
emtricitabine, and 1 mg to 1000 mg of the third active ingredient.
As a further feature of the present invention, a unitary dosage
form may further comprise tenofovir DF, emtricitabine, the third
active ingredient, or physiologically functional derivatives of the
three active ingredients thereof, and a pharmaceutically acceptable
carrier.
[0087] Combinations of the present invention enable patients
greater freedom from multiple dosage medication regimens and ease
the needed diligence required in remembering and complying with
complex daily dosing times and schedules. By combining tenofovir
disoproxil fumarate and emtricitabine into a single dosage form,
the desired daily regimen may be presented in a single dose or as
two or more sub-doses per day. The combination of co-formulated
tenofovir DF and emtricitabine may be administered as a single
pill, once per day.
[0088] A further aspect of the invention is a patient pack
comprising at least one active ingredient: tenofovir disoproxil
fumarate, emtricitabine, or a physiologically functional derivative
of either of the combination and an information package or product
insert containing directions on the use of the combination of the
invention.
[0089] Segregation of active ingredients in pharmaceutical powders
and granulations is a widely recognized problem that can result in
inconsistent dispersions of the active ingredients in final dosage
forms. Some of the main factors contributing to segregation are
particle size, shape and density. Segregation is particularly
troublesome when attempting to formulate a single homogenous tablet
containing multiple active ingredients having different densities
and different particle sizes. Glidants are substances that have
traditionally been used to improve the flow characteristics of
granulations and powders by reducing interparticulate friction. See
Lieberman, Lachman, & Schwartz, Pharmaceutical Dosage Forms:
Tablets, Volume 1, p. 177-178 (1989), incorporated herein by
reference. Glidants are typically added to pharmaceutical
compositions immediately prior to tablet compression to facilitate
the flow of granular material into the die cavities of tablet
presses. Glidants include: colloidal silicon dioxide, asbestos free
talc, sodium aluminosilicate, calcium silicate, powdered cellulose,
microcrystalline cellulose, corn starch, sodium benzoate, calcium
carbonate, magnesium carbonate, metallic stearates, calcium
stearate, magnesium stearate, zinc stearate, stearowet C, starch,
starch 1500, magnesium lauryl sulfate, and magnesium oxide.
Exemplary Tablet Formulation A has colloidal silicon dioxide
(Examples). Glidants can be used to increase and aid blend
composition homogeneity in formulations of anti-HIV drugs (U.S.
Pat. No. 6,113,920). The novel compositions of the present
invention may contain glidants to effect and maintain homogeneity
of active ingredients during handling prior to tablet
compression.
[0090] The present invention provides pharmaceutical formulations
combining the active ingredients tenofovir DF and emtricitabine, or
physiologically functional derivatives thereof, in a sufficiently
homogenized form, and a method for using this pharmaceutical
formulation. An object of the present invention is to utilize
glidants to reduce the segregation of active ingredients in
pharmaceutical compositions during pre-compression material
handling. Another object of the present invention is to provide a
pharmaceutical formulation combining the active ingredients
tenofovir DF and emtricitabine, or physiologically functional
derivatives thereof, with a pharmaceutically acceptable glidant,
resulting in a mixture characterized by a pharmaceutically
acceptable measure of homogeneity.
[0091] Formulations include those suitable for oral, rectal, nasal,
topical (including transdermal, buccal and sublingual), vaginal or
parenteral (including subcutaneous, intramuscular, intravenous and
intradermal) administration. The formulations may conveniently be
presented in unit dosage form and may be prepared by any methods
well known in the art of pharmacy. Such methods represent a further
feature of the present invention and include the step of bringing
into association the active ingredients with the carrier, which
constitutes one or more accessory ingredients, and maintaining
chemical stability. In general, the formulations are prepared by
uniformly and intimately bringing into association the active
ingredients with liquid carriers or finely divided solid carriers
or both, and then if necessary shaping the product.
[0092] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
caplets, cachets or tablets each containing a predetermined amount
of the active ingredients; as a powder or granules; as a solution
or a suspension in an aqueous or non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The
active ingredient may also be presented as a bolus, electuary or
paste.
[0093] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active
ingredients in a free-flowing form such as a powder or granules,
optionally mixed with a binder (e.g. povidone, gelatin,
hydroxypropyl methylcellulose), lubricant, inert diluent,
preservative, disintegrant (e.g. sodium starch glycollate,
cross-linked povidone, cross-linked sodium carboxymethyl cellulose)
surface-active or dispersing agent. Molded tablets may be made by
molding a mixture of the powdered compound moistened with an inert
liquid diluent in a suitable machine. The tablets may optionally be
coated or scored and may be formulated so as to provide slow or
controlled release of the active ingredients therein using, for
example, cellulose ether derivatives (e.g., hydroxypropyl
methylcellulose) or methacrylate derivatives in varying proportions
to provide the desired release profile. Tablets may optionally be
provided with an enteric coating, to provide release in parts of
the gut other than the stomach.
[0094] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredients in a
flavored base, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier. Formulations for
rectal administration may be presented as a suppository with a
suitable base comprising, for example, cocoa butter or a
salicylates. Topical administration may also be by means of a
transdermal iontophoretic device.
[0095] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0096] Formulations suitable for penile administration for
prophylactic or therapeutic use may be presented in condoms,
creams, gels, pastes, foams or spray formulations containing in
addition to the active ingredient such carriers as are known in the
art to be appropriate.
[0097] Pharmaceutical formulations suitable for rectal
administration wherein the carrier is a solid are most preferably
presented as unit dose suppositories. Suitable carriers include
cocoa butter and other materials commonly used in the art. The
suppositories may be conveniently formed by admixture of the active
combination with the softened or melted carrier(s) followed by
chilling and shaping in moulds.
[0098] Formulations suitable for parenteral administration include
aqueous and nonaqueous isotonic sterile injection solutions which
may contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents; and liposomes
or other microparticulate systems which are designed to target the
compound to blood components or one or more organs. The
formulations may be presented in unit-dose or multi-dose sealed
containers, for example, ampoules and vials, and may be stored in a
freeze-dried (lyophilized) condition requiring only the addition of
the sterile liquid carrier, for example water for injection,
immediately prior to use. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and
tablets of the kind previously described.
[0099] Exemplary unit dosage formulations are those containing a
daily dose or daily subdose of the active ingredients, as
hereinbefore recited, or an appropriate fraction thereof. It should
be understood that in addition to the ingredients particularly
mentioned above the formulations of this invention may include
other agents conventional in the art having regard to the type of
formulation in question, for example, those suitable for oral
administration may include such further agents as sweeteners,
thickeners and flavoring agents.
[0100] The compounds of the combination of the present invention
may be obtained in a conventional manner, known to those skilled in
the art. Tenofovir disoproxil fumarate can be prepared, for
example, as described in U.S. Pat. No. 5,977,089. Methods for the
preparation of FTC are described in WO 92/14743, incorporated
herein by reference.
Composition Use
[0101] Compositions of the present invention are administered to a
human or other mammal in a safe and effective amount as described
herein. These safe and effective amounts will vary according to the
type and size of mammal being treated and the desired results of
the treatment. Any of the various methods known by persons skilled
in the art for packaging tablets, caplets, or other solid dosage
forms suitable for oral administration, that will not degrade the
components of the present invention, are suitable for use in
packaging. The combinations may be packaged in glass and plastic
bottles. Tablets, caplets, or other solid dosage forms suitable for
oral administration may be packaged and contained in various
packaging materials optionally including a dessicant, e.g. silica
gel. Packaging may be in the form of unit dose blister packaging.
For example, a package may contain one blister tray of tenofovir DF
and another blister tray of emtricitabine pills, tablets, caplets,
or capsule. A patient would take one dose, e.g. a pill, from one
tray and one from the other. Alternatively, the package may contain
a blister tray of the co-formulated combination of tenofovir DF and
emtricitabine in a single pill, tablet, caplet or capsule. As in
other combinations and packaging thereof, the combinations of the
invention include physiological functional derivatives of tenofovir
DF and FTC.
[0102] The packaging material may also have labeling and
information related to the pharmaceutical composition printed
thereon. Additionally, an article of manufacture may contain a
brochure, report, notice, pamphlet, or leaflet containing product
information. This form of pharmaceutical information is referred to
in the pharmaceutical industry as a "package insert." A package
insert may be attached to or included with a pharmaceutical article
of manufacture. The package insert and any article of manufacture
labeling provides information relating to the pharmaceutical
composition. The information and labeling provides various forms of
information utilized by health-care professionals and patients,
describing the composition, its dosage and various other parameters
required by regulatory agencies such as the United States Food and
Drug Agency.
Assays of the Combinations
[0103] The combinations of the inventions may be tested for in
vitro activity against HIV and sensitivity, and for cytotoxicity in
laboratory adapted cell lines, e.g. MT2 and in peripheral blood
mononuclear cells (PBMC) according to standard assays developed for
testing anti-HIV compounds, such as WO 02/068058 and U.S. Pat. No.
6,475,491. Combination assays may be performed at varying
concentrations of the compounds of the combinations to determine
EC.sub.50 by serial dilutions.
Exemplary Formulations
[0104] The following examples further describe and demonstrate
particular embodiments within the scope of the present invention.
Techniques and formulations generally are found in Remington's
Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). The
examples are given solely for illustration and are not to be
construed as limitations as many variations are possible without
departing from spirit and scope of the Invention. The following
examples are intended for illustration only and are not intended to
limit the scope of the invention in any way. "Active ingredient"
denotes tenofovir disoproxil fumarate, emtricitabine, or a
physiologically functional derivative of either thereof.
Tablet Formulation
[0105] The following exemplary formulations A, B, C, D, E, and F
are prepared by wet granulation of the ingredients with an aqueous
solution, addition of extragranular components and then followed by
addition of magnesium stearate and compression.
[0106] Formulation A: TABLE-US-00002 mg/tablet Tenofovir Disoproxil
Fumarate 300 emtricitabine 200 Microcrystalline Cellulose 200
Lactose Monohydrate 175 Croscarmellose Sodium 60 Pregelatinized
Starch 50 Colloidal silicon dioxide 5 Magnesium Stearate 10 total:
1000
[0107] Formulation B: TABLE-US-00003 mg/tablet Tenofovir Disoproxil
fumarate 300 emtricitabine 100 Microcrystalline Cellulose 200
Lactose Monohydrate 180 Sodium Starch Glycollate 60 Pregelatinized
Starch 50 Magnesium Stearate 10 total: 900
[0108] Formulation C: TABLE-US-00004 mg/tablet Tenofovir Disoproxil
fumarate 200 emtricitabine 200 Microcrystalline Cellulose 200
Lactose Monohydrate 180 Sodium Starch Glycollate 60 Pregelatinized
Starch 50 Magnesium Stearate 10 total: 900
[0109] Formulation D: TABLE-US-00005 mg/tablet Tenofovir Disoproxil
fumarate 300 emtricitabine 25 Microcrystalline Cellulose 200
Lactose Monohydrate 180 Sodium Starch Glycollate 60 Pregelatinized
Starch 50 Magnesium Stearate 10 total: 825
[0110] Formulation E: TABLE-US-00006 mg/tablet Tenofovir Disoproxil
fumarate 200 emtricitabine 25 Microcrystalline Cellulose 200
Lactose Monohydrate 180 Sodium Starch Glycollate 60 Pregelatinized
Starch 50 Magnesium Stearate 10 total: 725
[0111] Formulation F: TABLE-US-00007 mg/tablet Tenofovir Disoproxil
fumarate 100 emtricitabine 100 Microcrystalline Cellulose 200
Lactose Monohydrate 180 Sodium Starch Glycollate 60 Pregelatinized
Starch 50 Magnesium Stearate 10 total: 700
Formulation G (Controlled Release Formulation):
[0112] This formulation is prepared by wet granulation of the
ingredients with an aqueous solution, followed by the addition of
magnesium stearate and compression. TABLE-US-00008 mg/tablet
Tenofovir Disoproxil fumarate 300 emtricitabine 200 Hydroxypropyl
Methylcellulose 112 Lactose B.P. 53 Pregelatinized Starch B.P. 28
Magnesium Stearate 7 total: 700
Drug release takes place over a period of about 6-8 hours and is
complete after 12 hours. Capsule Formulations Formulation H:
[0113] A capsule formulation is prepared by admixing the
ingredients and filling into a two-part hard gelatin or
hydroxypropyl methylcellulose capsule. TABLE-US-00009 mg/capsule
Active Ingredient 500 Microcrystalline Cellulose 143 Sodium Starch
Glycollate 25 Magnesium Stearate 2 total: 670
Formulation I (Controlled Release Capsule):
[0114] The following controlled release capsule formulation is
prepared by extruding ingredients a, b, and c using an extruder,
followed by spheronization of the extrudate and drying. The dried
pellets are then coated with release-controlling membrane (d) and
filled into a two-piece, hard gelatin or hydroxypropyl
methylcellulose capsule. TABLE-US-00010 mg/capsule (a) Active
Ingredient 500 (b) Microcrystalline Cellulose 125 (c) Lactose B.P.
125 (d) Ethyl Cellulose 13 total: 763
Formulation J (Oral Suspension):
[0115] The active ingredients are admixed with the ingredients and
filling them as dry powder. Purified water is added and mixed well
before use. TABLE-US-00011 Active Ingredient 500 mg Confectioner's
Sugar 2000 mg Simethicone 300 mg Methylparaben 30 mg Propylparaben
10 mg Flavor, Peach 500 mg Purified Water q.s. to 5.00 ml
Formulation K (Suppository):
[0116] One-fifth of the Witepsol H15 is melted in a steam-jacketed
pan at 45.degree. C. maximum. The active ingredients are sifted
through a 200 micron sieve and added to the molten base with
mixing, using a Silverson fitted with a cutting head, until a
smooth dispersion is achieved. Maintaining the mixture at
45.degree. C., the remaining Witepsol H15 is added to the
suspension and stirred to ensure a homogenous mix. The entire
suspension is passed through a 250 micron stainless steel screen
and, with continuous stirring, is allowed to cool to 40.degree. C.
At a temperature of 38.degree. C. to 40.degree. C., 2.02 g of the
mixture is filled into suitable, 2 ml plastic molds. The
suppositories are allowed to cool to room temperature.
TABLE-US-00012 mg/Suppository Active Ingredient 500 Hard Fat, B.P.
(Witepsol H15 - Dynamit Nobel) 1770 total 2270
Fixed Dose Combination Tablet
[0117] A fixed dose combination tablet of tenofovir disoproxil
fumarate (TDF) 300 mg/emtricitabine 200 mg was formulated using a
wet granulation/fluid-bed drying process using conventional
methods. See: U.S. Pat. No. 5,935,946; L. Young (editor). Tableting
Specification Manual 5.sup.th ed., American Pharmaceutical
Association, Washington, D.C., (2001); L. Lachman, H. Lieberman
(editors). Pharmaceutical Dosage Forms: Tablets (Vol 2), Marcel
Dekker Inc., New York, 185-202 (1981); J. T. Fell and J. M. Newton,
J. Pharm. Pharmacol. 20, 657-659 (1968); US Pharmacopeia
24-National Formulary 19, "Tablet Friability", Chapter
<1216>, Page 2148 (2000).
[0118] The effects of granulation water level (ranging from 40% to
50% w/w) and wet massing time were studied on the physicochemical
properties of the final powder blend and its performance with
respect to blend uniformity and compressibility (tablet
compactibility). In addition, content uniformity, assay, stability
and dissolution performance was evaluated for the TDF/emtricitabine
fixed dose combination tablets.
Formulation Equipment
[0119] Equipment included a high shear mixer equipped with a
pressure tank and spray nozzle tip to add the granulating water, a
fluid-bed dryer, a mill, a tumble blender, a rotary tablet press,
and a tablet deduster.
Formulation Process
[0120] The dried, milled powder was blended with the extragranular
microcrystalline cellulose and croscarmellose sodium and then
blended with magnesium stearate. Powder samples were removed after
mixing with the magnesium stearate. The blend samples were
evaluated for, bulk density, mesh analysis and compressibility. The
powder blend mixed with the magnesium stearate was compressed into
tablets on a press setup.
Materials
[0121] The following Table 1 lists the quantitative composition of
the TDF/emtricitabine tablet formulation. TABLE-US-00013 TABLE 1
Unit Formula for Quantity per tablet cores 12 kg Batch Ingredient %
w/w (mg/tablet) (kg) Tenofovir Disoproxil 30.0 300.0 3.60
Fumarate.sup.a Emtricitabine.sup.a 20.0 200.0 2.40 Pregelatinized
Starch, NF/EP 5.0 50.0 0.60 Croscarmellose Sodium, 6.0 60.0 0.72
NF/EP Lactose Monohydrate, NF/EP.sup.a 8.0 80.0 0.96
Microcrystalline Cellulose, 30.0 300.0 3.60 NF/EP.sup.c Magnesium
Stearate, NF/EP 1.0 10.0 0.12 Purified Water, USP/EP .sup.b .sup.b
.sup.b Totals 100.0 1000.0 12.00 .sup.a Actual weight is adjusted
based on the Drug Content Factor (DCF) of tenofovir disoproxil
fumarate and emtricitabine. .sup.b Water removed during drying.
Characterization Equipment
[0122] Moisture content was measured by loss on drying using a heat
lamp/balance system. The powder blend was sampled with a sampling
thief fitted with chambers to determine powder blend uniformity.
Duplicate samples were removed from each of several locations in
the blender. Blend uniformity analysis was performed on one sample
from each location.
[0123] Particle size analysis of the final powder blend was
determined by sifting a multi-gram sample through a screen using a
sonic sifter. The quantity of final powder blend retained on each
sieve and the fines collector was determined by calculating the
difference in weight between the sieves and fines collector before
and after the test. The geometric mean diameter particle size was
calculated by logarithmic weighting of the sieved distribution.
[0124] Bulk density was determined by filling a graduated cylinder
with the final powder blend and measuring the weight differential
between the empty and filled graduate cylinder per unit volume.
[0125] Tablets were characterized for friability using a
friabilator, a hardness tester, a thickness micrometer equipped
with a printer, and a weighing balance.
[0126] Compression characteristics were determined using a rotary
tablet press equipped with a flat-faced, beveled edged punch to a
target weight of 400 mg. The powder blends were compressed using
target upper punch pressures ranging from approximately 100 to 250
MPa. The apparent normalized ejection force was determined and
normalized for tablet thickness and diameter.
[0127] Tablet hardness was determined using a hardness tester.
Tablet thickness was determined using a micrometer, and tablet
weights were determined using a top loading balance.
Wet Granulation
[0128] The powders were blended in a granulator and then granulated
using water. The impeller and chopper speeds were kept constant in
the blender at a low setting during the granulation and wet massing
operations. After water addition, the impeller and chopper were
stopped and the granulator bowl was opened to observe the
granulation consistency and texture. The lid was closed and the wet
massing phase was performed. Acceptable granules had 40% w/w and
60% w/w water, respectively.
Wet Milling
[0129] To facilitate a uniform drying process, each wet granulation
was deagglomerated with a mill fitted with a screen and an
impeller. The milled wet granules were charged into a fluid-bed
dryer immediately following wet milling.
Fluid-Bed Drying
[0130] Milled wet granules were dried using an inlet air setpoint
temperature of about 70.degree. C. and airflow of approximately 100
cfm. The target LOD was about 1.0% with a range of not more than
(NMT) 1.5%. The total fluid-bed drying time ranged from 53 to 75
minutes. Final LOD ranged from 0.4% to 0.7% for all of the batches
dried. The final exhaust temperatures for all the batches ranged
from 47.degree. C. to 50.degree. C.
Dry Milling
[0131] All dried granules were milled through a perforated screen.
The mill was equipped with a square impeller and operated. The lots
were milled and manually transferred to the V-blender.
Blending
[0132] Each lot was blended using the V-blender. In one set of
three formulations, starting with 12 kg materials, final powder
blend yield available for compression after blending ranged from
10.5 kg (87.5%) to 11.1 kg (92.5%). The final powder blend bulk
density ranged from 0.48 to 0.58 g/cc and the geometric mean
diameter particle size ranged from 112 to 221 .mu.m. Percent water
and wet massing time affect final powder blend particle size and
bulk density.
[0133] The powder blending for both tenofovir DP and emtricitabine
gave a mean (n=10) strength value for tenofovir DF ranged from
100.6% to 102.8% of target strength for the lots and the relative
standard deviation (RSD) was from 0.5% to 1.7%. The mean (n=10)
strength value for emtricitabine ranged from 101.3% to 104.1% of
target strength for the lots with the relative standard deviation
(RSD) ranged from 0.6% to 1.7%. The final powder blend moisture
level ranged from 0.8% to 1.1% LOD.
Tablet Compression
[0134] The final blends were compressed using a rotary tablet press
and the tablets were film-coated.
[0135] Three 300 gm formulations (Table 2) were granulated in a
granulator equipped with a 1-L bowl. The quantities of
intragranular components were based on a 300 g total batch size.
The formulations in lots 1 and 2 differed in the amount of
microcrystalline cellulose 30% vs. 20% w/w, respectively. Lots 2
and 3 were identical except for the type of binder. Lot 2 contained
5% w/w of pregelatinized starch and lot 3 contained 5% w/w povidone
as binder. TABLE-US-00014 TABLE 2 Lot 1 Lot 2 Lot 3 Ingredient %
w/w % w/w % w/w Tenofovir Disoproxil Fumarate 30.0 30.0 30.0
Emtricitabine 20.0 20.0 20.0 Pregelatinized Starch, NF/EP 5.0 5.0
N/A Povidone, USP/NF (C-30) N/A N/A 5.0 Croscarmellose Sodium,
NF/EP 6.0 6.0 6.0 Lactose Monohydrate, NF/EP 8.0 18.0 18.0
Microcrystalline Cellulose, 30.0 20.0 20.0 NF/EP.sup.a Magnesium
Stearate, NF/EP 1.0 1.0 1.0 Purified Water, USP/EP .sup.a .sup.a
.sup.a Total 100.0 100.0 100.0 .sup.a Water removed during
drying.
[0136] After water addition, the impeller and chopper were stopped
and the granulator bowl was opened to observe the granulation
consistency and texture. To achieve similar granulation
consistency, lots 1, 2, and 3 were granulated with 45%, 40%, and
30% w/w water, respectively. The lid was closed and the wet massing
phase was performed. All lots had a 30 sec wet massing resulting in
acceptable granulations. The wet granulations from all batches were
hand screened through a sieve to deagglomerate. The resulting
granulations were tray dried in a convection oven set at 60.degree.
C. for approximately 20 hours to an LOD <1.0%. The dried
granulations from all batches were hand screened through a sieve.
In order to fit the granulation into the small scale (300 mL)
V-blender, the final blend batch size was adjusted to 100 g. A
portion, 81 g of the resulting blend from Lot 1 was blended with 15
g microcrystalline cellulose, 3 g croscarmellose sodium and 1 g
magnesium stearate. 86 g of the resulting granulation from Lot 2
and Lot 3 were each blended with 10 g microcrystalline cellulose, 3
g croscarmellose sodium and 1 g magnesium stearate.
[0137] Purity analysis was conducted by reverse-phase HPLC (high
performance liquid chromatography). Impurities related to tenofovir
disoproxil fumarate and emtricitabine were characterized and
measured in the bulk API (active pharmaceutical ingredient) before
formulation in the three lots of Table 2, and again after
formulation in the resulting tablets. The impurities include
by-products from hydrolysis of the exocyclic amino groups of
tenofovir disoproxil fumarate and emtricitabine, and the hydrolysis
of the disoproxil (POC) esters of tenofovir disoproxil fumarate. In
each lot, the sum total of impurities related to tenofovir
disoproxil fumarate and emtricitabine was less than 1% after
formulation and tablet manufacture.
[0138] The physicochemical properties of tenofovir disoproxil
fumarate and emtricitabine tablets were evaluated by visual
appearance, water content, label strength, impurity and degradation
product contents, and tablet dissolution. Stability studies were
conducted on drug product packaged in container-closure systems
that are identical to the intended clinical and commercial
container-closure system. There was no sign of discoloration or
tablet cracking during the course of the stability study.
Film-coated tenofovir disoproxil fumarate and emtricitabine tablets
exhibited satisfactory stability at 40.degree. C./75% RH (relative
humidity) for up to six months when packaged and stored with silica
gel desiccant. No significant loss (defined as >5% degradation)
in % label strength of tenofovir DF or emtricitabine was observed
after six months at 40.degree. C./75% RH. when packaged and stored
with desiccant. The increase in the total degradation products was
1.5% for tenofovir DF and 0.6-0.7% for emtricitabine after six
months at 40.degree. C./75% RH when packaged and stored with 3
grams of desiccant.
[0139] All publications and patent applications cited herein are
incorporated by reference to the same extent as if each individual
publication or patent application was specifically and individually
indicated to be incorporated by reference.
[0140] Although certain embodiments are described in detail above,
those having ordinary skill in the art will clearly understand that
many modifications are possible in the claims without departing
from the teachings thereof. All such modifications are intended to
be encompassed within the claims of the invention.
Embodiments of the Invention
[0141] A1. A pharmaceutical composition comprising an effective
amount of a compound of the formula: ##STR8##
[0142] wherein R.sup.1 and R.sup.2 are independently selected from
H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted alkyl,
C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted aryl,
C.sub.6-C.sub.20 arylalkyl, C.sub.6-C.sub.20 substituted arylalkyl,
acyloxymethyl esters --CH.sub.2C(.dbd.O)R.sup.9 and acyloxymethyl
carbonates --CH.sub.2C(.dbd.O)OR.sup.9 where R.sup.9 is
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted alkyl,
C.sub.6-C.sub.20 aryl and C.sub.6-C.sub.20 substituted aryl;
[0143] R.sup.3 is selected from H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 substituted alkyl, or CH.sub.2OR.sup.8 where
R.sup.8 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 hydroxyalkyl and
C.sub.1-C.sub.6 haloalkyl;
[0144] R.sup.4 and R.sup.5 are independently selected from H,
NH.sub.2, NHR and NR.sub.2 where R is C.sub.1-C.sub.6 alkyl;
and
[0145] R.sup.6 and R.sup.7 are independently selected from H and
C.sub.1-C.sub.6 alkyl;
[0146] or a physiologically functional derivative thereof;
[0147] in combination with an effective amount of a compound of the
formula ##STR9##
[0148] wherein B is selected from adenine, guanine, cytosine,
uracil, thymine, 7-deazaadenine, 7-deazaguanine,
7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine,
nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine,
2,6-diaminopurine, hypoxanthine, pseudouridine, 5-fluorocytosine,
5-chlorocytosine, 5-bromocytosine, 5-iodocytosine, pseudocytosine,
pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine,
7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine,
4-thiouracil, O.sup.6-methylguanine, N.sup.6-methyladenine,
O.sup.4-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil,
4-methylindole, and a pyrazolo[3,4-D]pyrimidine; and
[0149] R is selected from H, C.sub.1-C.sub.18 alkyl,
C.sub.1-C.sub.18 is substituted alkyl, C.sub.2-C.sub.18 alkenyl,
C.sub.2-C.sub.18 substituted alkenyl, C.sub.2-C.sub.18 alkynyl,
C.sub.2-C.sub.18 substituted alkynyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heterocycle,
C.sub.2-C.sub.20 substituted heterocycle, phosphonate,
phosphophosphonate, diphosphophosphonate, phosphate, diphosphate,
triphosphate, polyethyleneoxy or a physiologically functional
derivative thereof; and
[0150] a pharmaceutically acceptable carrier.
[0151] B2. A composition of embodiment A1 wherein, in formula 1,
R.sup.1 and R.sup.2 are independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted alkyl,
C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted aryl,
C.sub.6-C.sub.20 arylalkyl, C.sub.6-C.sub.20 substituted arylalkyl,
acyloxymethyl esters --CH.sub.2C(.dbd.O)R.sup.9 and acyloxymethyl
carbonates --CH.sub.2C(.dbd.O)OR.sup.9 where R.sup.9 is
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted alkyl,
C.sub.6-C.sub.20 aryl and C.sub.6-C.sub.20 substituted aryl; and
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are independently H
or C.sub.1-C.sub.6 alkyl.
C3. A composition of embodiment A1 wherein, in formula 2, B is
cytosine or a 5-halocytosine.
[0152] D4. A composition of embodiment A1 wherein, in formula 1,
R.sup.1 and R.sup.2 are independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted alkyl,
C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted aryl,
C.sub.6-C.sub.20 arylalkyl, C.sub.6-C.sub.20 substituted arylalkyl,
acyloxymethyl esters --CH.sub.2C(.dbd.O)R.sup.9 and acyloxymethyl
carbonates --CH.sub.2C(.dbd.O)OR.sup.9 where R.sup.9 is
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted alkyl,
C.sub.6-C.sub.20 aryl and C.sub.6-C.sub.20 substituted aryl; and
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are independently H
or C.sub.1-C.sub.6 alkyl; and, in formula 2, B is cytosine or a
5-halocytosine.
[0153] E5. A composition of embodiment D 4 wherein, in formula 1,
R.sup.1 and R.sup.2 are independently selected from H,
acyloxymethyl esters --CH.sub.2OC(--O)R.sup.9 and acyloxymethyl
carbonates --CH.sub.2C(.dbd.O)OR.sup.9 where R.sup.9 is
C.sub.1-C.sub.6 alkyl; and R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 are independently H or C.sub.1-C.sub.6 alkyl; and, in
formula 2, B is cytosine or a 5-halocytosine and R is H.
F6. A composition of embodiment E5 wherein, in formula 1, R.sup.1
and R.sup.2 are independently selected from H and
--CH.sub.2C(.dbd.O)OCH(CH.sub.3).sub.2; R.sup.3 is --CH.sub.3; and
R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are H; and, in formula 2, B
is 5-fluorocytosine and R is H.
[0154] G7. A pharmaceutical composition comprising a
pharmaceutically effective amount of
[2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid
diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil
fumarate) or a physiologically functional derivative thereof and a
pharmaceutically effective amount of (2R,
5S,)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimi-
din-2-one (emtricitabine) or a physiologically functional
derivative thereof; and a pharmaceutically acceptable carrier.
[0155] H8. A pharmaceutical formulation of embodiment A1 to G7
further comprising a third active ingredient selected from the
group consisting of a protease inhibitor, a nucleoside or
nucleotide reverse transcriptase inhibitor, a non-nucleoside
reverse transcriptase inhibitor, and an integrase inhibitor.
I9. A pharmaceutical formulation of embodiments A1 to H8 in unit
dosage form.
J10. A method for the treatment or prevention of the symptoms or
effects of an HIV infection in an infected animal which comprises
administering to said animal a pharmaceutical composition of
embodiments claims A1 to I9.
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