Note: Descriptions are shown in the official language in which they were submitted.
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= UNIT DOSAGE FORM COMPRISING EMTRICITABINE, TENOFOVIR,
DARUNAVIR AND RITONAVIR AND A MONOLITHIC TABLET COMPRISING
DARUNAVIR AND RITONAVIR
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No.
61/871,674
entitled "UNIT DOSAGE FORM COMPRISING EMTRICITABINE, TENOFOVIR,
DARUNAVIR AND RITONAVIR AND A MONOLITHIC TABLET COMPRISING
DARUNAVIR AND RITONAVIR," filed on August 29, 2013, the contents of which are
incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to an oral unit dosage form comprising
emtricitabine,
tenofovir, darunavir and ritonavir and to a monolithic tablet comprising
darunavir and
ritonavir and their use to treat HIV infection. The invention further relates
to methods of
preparing the oral dosage forms containing the above pharmaceutical active
agents.
BACKGROUND OF THE INVENTION
Tenofovir, the systematic chemical name for which is ({[(2R)-1-(6-amino-9H-
purin-
9-y1) propan-2-yl] oxy} methyl) phosphonic acid, is a nucleoside reverse
transcriptase
inhibitor (NRTI) which is used to treat infection by HIV-I. Its synthesis,
analogs,
formulation and use are described in various publications including, inter
alia, U.S. Patent
Nos. 5,922,695; 5,935,946, 5,977,089 and 6, 043, 230.
Pharmaceutical formulations comprising combinations of tenofovir and another
non-
nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor
(PI) are
described in various publications including, inter alia, US 8, 592, 397, US 8,
716, 264 and
US20140037732.
Tenofovir disoproxil fumarate (TDF) is a prodrug form of tenofovir. TDF is
marketed by Gilead Sciences under the trade name VIREAD . VIREAD tablets are
available in strengths of 150, 200, 250, and 300 mg of tenofovir disoproxil
fumarate, which
are equivalent to 123, 163, 204 and 245 mg of tenofovir disoproxil,
respectively. The tablet
also includes the following inactive ingredients: croscarmellose sodium,
lactose
monohydrate, magnesium stearate, microcrystalline cellulose, and
pregelatinized starch.
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Tenofovir is also available in a fixed-dose combination with emtricitabine in
a
product with the brand name TRUVADA , which has been approved for once-a-day
dosing. Each TRUVADA tablet contains 200 mg of emtricitabine and 300 mg of
tenofovir
disoproxil fumarate, (which is equivalent to 245 mg of tenofovir disoproxil),
as active
ingredients. The tablets also include the following inactive ingredients:
croscarmellose
sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose,
and
pregelatinized starch. The total weight of the TRUVADA tablet is 1045mg,
having the
dimensions of 19 mm x 8.5 mm.
Emtricitabine, the systematic chemical name for which is 4-amino-5-fluoro-1-
[2-
(hydroxymethyl)-1, 3-oxathiolan-5-y1]-pyrimidin-2-one, is another nucleoside
reverse
transcriptase inhibitor (NRTI) which is used to treat infection by HIV-I. Its
synthesis and
use are described in various publications including, inter alia, U.S. Patent
Nos. 5,210,085;
5,814,639; 5,914,331, 6, 642, 245 and 7,402,588.
Emtricitabine (FTC) is marketed by Gilead Sciences under the trade name
EMTRIVA . EMTRIVA is available as capsules or as an oral solution. Each
capsule
contains 200 mg of emtricitabine and also the following inactive ingredients:
crospovidone,
magnesium stearate, microcrystalline cellulose, povidone, titanium dioxide,
gelatin, and
FD&C blue No. 2.
Darunavir, the systematic name for which is [(1R,55,6R)-2,8-
dioxabicyclo[3.3.0]oct-6-yl] N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-
methylpropyl)amino]-3-hydroxy-l-phenyl-butan-2-yl] carbamate, is another
antiretroviral
drug of the protease inhibitor (PI) class which is used to treat HIV-I. Its
synthesis, use,
salts, formulation and combinations thereof are described in various
publications including
U.S. Patent Nos. 6,335,460; 6,248,775, 5,843,946, USRE43596 and W02013004816.
Darunavir is marketed by Tibotec (Janssen) under the trade name PREZISTA .
PREZISTA tablets are available in strengths of 75 mg, 150 mg, 400 mg, 600 mg,
and 800
mg. Each tablet also contains the inactive ingredients colloidal silicon
dioxide,
crospovidone, magnesium stearate, and microcrystalline cellulose. The 800 mg
tablet also
contains hypromellose. The total weight of the PREZISTA 800 mg tablet is 1048
mg,
having the dimensions of 20 mm x 8 mm.
Ritonavir, the systematic chemical name for which is 1,3-thiazol-5-ylmethyl N-
[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methy1-2-{[methyl({[2-(propan-2-y1)-1,3-
thiazol-4-
yl]methyll)carbamoyl]aminolbutanamido]-1,6-diphenylhexan-2-yl]carbamate, is
another
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antiretroviral drug of the protease inhibitor (PI) class which is used to
treat infection by
HIV-T. Its synthesis use, formulation and combinations thereof are described
in various
publications including, inter alia, U.S. Patent Nos. 5,541,206; 5,648,497,
6,037,157, 7,
364, 752 and US8, 268, 349.
Ritonavir is marketed by Abbott Laboratories under the trade name NORVIR .
Norvire is available as 100 mg tablet or capsule and as an 80mg/m1 oral
solution. Ritonavir
is BCS (biopharmaceutical classification system) class IV material. Thus,
ritonavir has very
low solubility and permeability. Abbott developed Norvir0 tablet, using an
amorphous
ritonavir in a hot melt extrusion manufacturing process, with a high amount of
polymer
(NDA 22-417- chemistry review,
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022417s000_ChemR.pdf).
The
Norvir tablet contains: 100 mg ritonavir, copovidone, sorbitan laurate,
calcium hydrogen
phosphate anhydrous, anhydrous colloidal silica, sodium stearyl fumarate and
are coated
with a film-coating formed of hypromellose, titanium dioxide (E171),
macrogols,
hydroxypropyl cellulose, talc, anhydrous colloidal silica and polysorbate 80.
The total
weight of Norvir0 tablet is 800mg, and the tablet has dimensions of
17.2x5.8mm.
Administered alone, most antiretroviral agents have proved only partially
effective,
often unable to block HIV replication sufficient to obtain an optimal
reduction in viral load
or prevent its rise.
To overcome this deficiency, highly active antiretroviral therapy (HAART) has
been
developed over the years. HAART consists of co-administration of three
antiretroviral
agents. The three drugs may be administered separately or administered as a
unit dosage
form containing three active ingredients.
Administration of three or four active ingredients, for the treatment of human
immunodeficiency virus (HIV) in humans, was suggested in WO 2011/061302 and WO
2011/061303. The manufacture of triple fixed dose combinations are disclosed
in WO
1996/030025 and WO 2006/135933.
W02009/081174 describes a dual combination formulation of ritonavir and
darunavir; wherein ritonavir is in a first layer and darunavir is in a second
layer. According
to this disclosure, ritonavir and darunavir, when admixed, results in
incompatibilities in
which the stability of the active agents is compromised. Accordingly,
W02009/081174
discloses that the two active agents must be separated from each other, i.e.,
by the provision
of a composition in which each agent is present in separate layers.
Nevertheless, from the
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point of view of ease of manufacture, monolithic compositions are generally
preferred over
multilayer compositions. However, the successful formulation of monolithic
dosage forms,
is dependent on ensuring that the stability of the active agents in the dosage
form is not
compromised, as well as ensuring that the dosage form is of a size that
enables it to be
easily administered.
W02013057469 describes a combination composition in a kit form. The kit can
comprise separate unit dosage forms of various antiretroviral drugs with a set
of instructions
for their administration. Nevertheless, the administration of separate dosage
forms in
accordance with a set of instructions does not provide an optimal improvement
of patient
compliance, especially if the dosage forms are to be taken at different times.
Moreover, the
instructions may be misplaced, or may be incorrectly followed by the patient.
There is thus a need to provide a chemically stable dosage form containing
ritonavir
and darunavir which has the advantage of ease of manufacture. There is an
additional need
to provide dosage forms in which combinations of antiretroviral drugs such as
emtricitabine, tenofovir, darunavir and ritonavir, are provided in a
composition that can be
readily administered so as to further improve patient compliance. In
particular, there is a
need for less onerous dosage regimen, such as once daily oral dosing,
optimally, in a one
pill, having the required stability and bioavailability.
The present invention addresses for the first time the preparation of a unit
dose form
containing emtricitabine, tenofovir, darunavir and ritonavir and of a
monolithic tablet
containing darunavir and ritonavir
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a pharmaceutical formulation in
a unit
dosage form comprising:
tenofovir or a physiologically functional derivative thereof,
emtricitabine or a physiologically functional derivative thereof,
darunavir or a physiologically functional derivative thereof, and
ritonavir or a physiologically functional derivative thereof.
In a further aspect, the present invention provides a monolithic tablet
comprising:
darunavir or a physiologically functional derivative thereof and
ritonavir or a physiologically functional derivative thereof
The present invention further provides the above unit dose formulation or the
above
monolithic tablet for use as a medicament.
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The present invention further provides the above unit dose formulation or the
above
monolithic tablet for use in the treatment of HIV-1 infection.
The present invention further provides a method for treating HIV-1 infection
comprising administration of a pharmaceutically effective amount of the above
unit dose
formulation or of the above monolithic tablet.
DETAILED DESCRIPTION OF THE INVENTION
Unless stated otherwise, the following terms and phrases as used herein are
intended
to have the following meanings:
The compounds or their combinations of the invention may be referred to as
"active
ingredients" or "pharmaceutically active agents."
The term "physiologically functional derivative" includes any:
pharmaceutically
acceptable salts, pharmaceutically acceptable enantiomers, pharmaceutically
acceptable
solid state form (crystalline, semi-crystalline or amorphous),
pharmaceutically acceptable
polymorphs, pharmaceutically acceptable solvates, pharmaceutically acceptable
metabolites
or pharmaceutically acceptable prodrugs thereof (for example, wherein the
prodrug is an
ester), or a pharmaceutically acceptable salt of the enantiomer, solid state
form, polymorph,
solvate, metabolite or prodrug (e.g. an ester prodrug).
The terms "Emtricitabine", "Tenofovir", "Darunavir" and "Ritonavir" are
mentioned
throughout in a broad sense to include not only emtricitabine, tenofovir,
darunavir and
ritonavir, per se, but also their physiologically functional derivatives.
Preferably in any
embodiment or any aspect of the present invention, the tenofovir is in the
form of its
product, tenofovir disoproxil. More preferably the tenofovir disoproxil is in
the form of its
fumarate salt, i.e. tenofovir disoproxil fumarate. Preferably in any
embodiment or any aspect
of the present invention, the darunavir is in the form of darunavir or its
physiologically
functional derivatives, e.g. darunavir can be darunavir ethanolate, hydrate,
or any other
crystalline form as well as amorphous darunavir.
Preferably in any embodiment or any aspect of the present invention, the
ritonavir is
in the form of ritonavir or its physiologically functional derivatives. More
preferably the
ritonavir is in the form of its crystalline form as well as amorphous
ritonavir, i.e., crystalline
form can be for example, Form I or Form II, substantially as described in
EP1097148.
Characteristic peaks of in the powder X-ray diffraction pattern of Ritonavir
Form I can be
found in 3.33 0.1 , 6.76 0.1 , 8.33 0.1 , 14.61 0.1 , 16.33 0.1
, 16.76 0.1 ,
17.03 0.1 , 18.02 0.1 , 18.62 0.1 , 19.47 0.1 , 19.86 0.1 ,
20.25 0.1 ,
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21.46 0.10, 23.46 0.1 and 24.36 0.1 (two theta). Characteristic
peaks of in the
powder X-ray diffraction pattern of Ritonavir Form II can be found in 8.67
0.1 ,
9.88 0.1 , 16.110 0.10, 16.70 0.1 , 17.36 0.1 , 17.78 0.1 , 18.40 0.1 ,
18.93 0.1 ,
20.07 0.1 , 20.65 0.1 , 21.71 0.1 and 25.38 0.1 (two theta).
Unless otherwise indicated, a reference to weight% of the dosage form mean the
weight% relative to the weight of the dosage form excluding, in the case of a
tablet, any
finishing/cosmetic coating, and in the case of a capsule, the weight of the
dosage form
refers to the total weight of the capsule contents, i.e. excluding the capsule
shell.
The term "chemical stability" means that the active ingredients in the
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. Preferably "chemically stable" in any embodiment
of any
aspect of the present invention, the term "chemically stable" refers to a
formulation which,
when stored at 40 C and at 75% relative humidity for 1 month to 6 months, the
amounts of
each of darunavir and ritonavir; and/or the amount of each of tenofovir and
emtricitabine,
do not significantly diminish compared with the amounts of each of darunavir
and ritonavir
; and/or the amount of each of tenofovir and emtricitabine, in the formulation
prior to
storage.
In particular, a formulation according to any aspect or embodiment of the
present
invention may be considered to be chemically stable if at least about 97%,
preferably at
least about 98%, more preferably at least about 99%, most preferably at least
about 99.5%,
and especially at least about 99.9% of each of the darunavir and ritonavir
content, and/or
each of tenofovir and emtricitabine content in the formulation immediately
before storage is
retained after storage at 40 C and at 75% relative humidity for 1 month to 6
months.
Preferably, in accordance with any aspect or embodiment of the present
invention, the term
"chemically stable" refers to a formulation in which from about 90% to about
100%, about
95% to about 100%, about 98% to about 100%, about 99% to about 100%, 99.5% to
about
100% or 99.9% to about 100% of each of the darunavir and ritonavir content
and/or each of
tenofovir and emtricitabine content in the formulation immediately before
storage is
= retained following storage of the formulation at 40 C and at 75% relative
humidity for 1
month to 6 months. More preferably, about 99.95% to about 100% is retained. In
a
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particularly preferred embodiment of the present invention, the term
"chemically stable"
refers to a formulation in which at least about 99.95% of each of the
darunavir and ritonavir
content and/or each of tenofovir and emtricitabine content in the formulation
immediately
before storage is retained after storage at 40 C and at 75% relative humidity
for 1 month to
6 months. In especially preferred embodiments of the present invention, the
term
"chemically stable" refers to a formulation in which there is no detectable
change in the
darunavir and ritonavir content and/or each of tenofovir and emtricitabine
content, in the
formulation immediately before storage and after storage at 40 C and at 75%
relative
humidity for 1 month to 6 months.
Any change in the darunavir and ritonavir contents, and/or tenofovir and
emtricitabine contents of the formulations can be measured by standard
analytical
techniques well known to the skilled person. HPLC is a preferred method for
this purpose.
For example, an HPLC assay using standard solutions may be employed, an
example of
which is set out below.
Reference to weight % or % by weight of pharmaceutically acceptable salts of
emtricitabine, tenofovir, darunavir and ritonavir refer to the amount relative
to the free base
form. Where the emtricitabine, tenofovir, darunavir and/or ritonavir is in the
form of a
prodrug, the weight % refers to the amount relative to the form of the
prodrug. Thus, for
example, reference to weight% of tenofovir disoproxil fumarate is the amount
relative to
tenofovir disoproxil.
The term "bioavailability" means the rate and extent to which the active
ingredient
or active moiety is absorbed from a drug product and becomes available at the
site of action.
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.
The bioavailability of a pharmaceutical composition can be determined, for
example, by any pharmacokinetic parameter known to the person skilled in the
art.
Examples of such parameters include: t112 (half-life), Cmin (minimal plasma
concentration),
C trough concentration, Cm), (maximal plasma concentration), AUC (area under
the curve),
Tmax (time to maximal concentration), and Cõ (steady state concentration).
The assessment of same/comparable pharmacokinetic bioavailability can be based
on 90% confidence intervals for the ratio of the population geometric means
(test/reference)
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for the parameters under consideration. This method can be equivalent to two
one-sided
tests with the null hypothesis of bioinequivalence at the 5% significance
level.
The pharmacokinetic parameters under consideration can be analyzed using
ANOVA. The data can be transformed prior to analysis using a logarithmic
transformation.
A confidence interval for the difference between formulations on the log-
transformed scale
can be obtained from the ANOVA model. This confidence interval can then back-
transformed to obtain the desired confidence interval for the ratio on the
original scale.
Ritonavir, may be used as `pharmacokinetic enhancer' (booster) to increase the
blood levels of darunavir. Accordingly, the bioavailability of darunavir may
be compared to
the bioavailability of the commercial darunavir when administered with the
commercial
ritonavir (Norvir ) as a pharmacokinetic enhancer.
The references hereinafter to a pharmaceutical formulation refer unless
otherwise
stated to a pharmaceutical formulation containing the combination or also
their
physiologically functional derivatives.
The unit dosage form of the 4 APIs 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, emtricitabine, darunavir and ritonavir into a single dosage form,
the desired
daily regimen may be presented in a single dose per day. The pharmaceutical
formulations
of co-formulated tenofovir, emtricitabine, darunavir, and ritonavir may be
administered as a
single dose form, once per day.
Ideally the pharmaceutical formulation should be administered to achieve peak
plasma concentrations of each of the compounds/active pharmaceutical
ingredients when
administered in a separated unit doses containing each one of the active
pharmaceutical
ingredients separately, while avoiding compromising the stability and the size
of the
pharmaceutical formulation.
The pharmaceutical formulation may be formulated in a unit dosage formulation
comprising an amount of each compound/active pharmaceutical ingredient that is
suitable
for a daily dose to ensure the desired therapeutic effect.
The present invention provides a pharmaceutical formulation in a unit dosage
form
comprising:
tenofovir or a physiologically functional derivative thereof,
emtricitabine or a physiologically functional derivative thereof,
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darunavir or a physiologically functional derivative thereof and
ritonavir or a physiologically functional derivative thereof;
The above pharmaceutical formulation comprising tenofovir disoproxil or a
physiologically functional derivative thereof, emtricitabine or a
physiologically functional
derivative thereof, darunavir or a physiologically functional derivative
thereof and ritonavir
or a physiologically functional derivative thereof can be chemically stable.
The total weight of the pharmaceutical formulation of the present invention,
comprising the above 4 APIs, can be less than or equal to about 2.800g, less
than or equal to
about 2.600g, less than or equal to about 2.500g,less than or equal to about
2.400g, less than
or equal to about 2.300g, less than or equal to about 2.200g, less than or
equal to about
1.900g or less than or equal to about 1.800g, or less than or equal to about
1.700g, or less
than or equal to about 1.600g, or less than or equal to about 1.500g. In a
specific
embodiment of the present invention the total dosage form weight is between
1.500g to
about 1.600g, to about 1.700g, to about 1.800g, to about 1.900g, to about
2.000g, to about
2.200g, to about 2.300g, to about 2.400g, to about 2.500g, to about 2.600g, to
about 2.800g,
or between 1.600g, to about 1.700g, to about 1.800g, to about 1.900g, to about
2.000g, to
about 2.200g, to about 2.300g, to about 2.400g, to about 2.500g, to about
2.600g, to about
2.800g, or between 1.700g, to about 1.800g, to about 1.900g, to about 2.000g,
to about
2.200g, to about 2.300g, to about 2.400g, to about 2.500g, to about 2.600g, to
about
2.800g,or between 1.800g, to about 1.900g, to about 2.000g, to about 2.200g,
to about
2.300g, to about 2.400g, to about 2.500g, to about 2.600g, to about 2.800g, or
between
1.900g, to about 2.000g, to about 2.200g, to about 2.300g, to about 2.400g, to
about 2.500g,
to about 2.600g, to about 2.800g,or between 2.000g to about 2.200g, to about
2.300g, to
about 2.400g, to about 2.500g, to about 2.600g, to about 2.800g, or between
about 2.200g,
to about 2.300g, to about 2.400g, to about 2.500g, to about 2.600g, to about
2.800g, or
between about 2.300g, to about 2.400g, to about 2.500g, to about 2.600g, to
about 2.800g,
or between about 2.400g, to about 2.500g, to about 2.600g, to about 2.800g, or
between
about 2.500g, to about 2.600g, to about 2.800g, or between about 2.600g to
about 2.800g.
By way of example, the pharmaceutical formulation of the present invention
comprises about 150 mg to 350mg of tenofovir disoproxil fumarate, about 100mg
to 300mg
of emtricitabine, about 75mg to 800mg of darunavir and about 100mg of
ritonavir. The
amount of darunavir can be 75mg, 150mg, 300mg, 400mg 600mg, or 800mg
(corresponding to the doses of commercially available of Prezistat). The said
darunavir can
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be darunavir ethanolate, hydrate, or any other crystalline form as well as
darunavir
amorphous. The amount of ritonavir can be 100mg of ritonavir (corresponding to
the dose
of the commercially available of Norvire tablet).
Preferably, the pharmaceutical formulation of the present invention comprises
about
300mg of tenofovir disoproxil fumarate, about 200mg of emtricitabine, about
800mg of
darunavir and about 100mg of ritonavir.
In certain embodiments, the pharmaceutical formulation of the present
invention
comprises from about 20% to about 85% by weight of total weight of all 4
pharmaceutically
active ingredients. The pharmaceutical formulation of the present invention
comprises from
about 20% to about 25%, to about 30%, to about 35%, to about 40%, to about
45%, to about
50%, to about 55%, to about 60%, to about 65%, to about 70%, to about 75%, to
about
80%, or to about 85% by weight of total weight of all 4 pharmaceutically
active ingredients,
or from about 25% to about 30%, to about 35%, to about 40%, to about 45%, to
about 50%,
to about 55%, to about 60%, to about 65%, to about 70%, to about 75%, to about
80%, or to
about 85%, or from about 30% to about 35%, to about 40%, to about 45%, to
about 50%, to
about 55%, to about 60%, to about 65%, to about 70%, to about 75%, to about
80%, or to
about 85%, or from about 40% to about 45%, to about 50%, to about 55%, to
about 60%, to
about 65%, to about 70% , to about 75%, to about 80%, or to about 85%, or from
about
45% to about 50%, to about 55%, to about 60%, to about 65%, to about 70%, to
about 75%,
to about 80%, or to about 85%, or from about 50% to about 55%, to about 60%,
to about
65%, to about 70%, to about 75%, to about 80%, or to about 85% or from about
55%, to
about 60%, to about 65%, to about 70%, to about 75%, to about 80%, or to about
85%, or
from about 60% to about 65%, to about 70%, to about 75%, to about 80%, or to
about 85%,
or from about 65% to about 70%, to about 75%, to about 80%, or to about 85%,
or from
about 70% to about 75%, to about 80%, or to about 85%, or from about 75%, to
about 80%,
or to about 85%, or from about 80% to about 85% by weight of all 4
pharmaceutically
active ingredients.
The pharmaceutical formulation of the present invention can be suitable for
oral
administration. Oral dosage forms for the purpose of the present invention
include capsules,
tablets, pellets, granules, powders and pharmaceutical formulations thereof
For example,
the pharmaceutical composition can be formulated in the form of coated or
uncoated,
effervescent, soluble, orodispersible, enteric or modified-release tablets;
sugar-coated
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tablets; hard capsules; soft capsules; granules; pills; pastilles. Preferably,
the oral dosage
form is a tablet. The tablet can be chemically stable.
The tablet can have a weight as mentioned above for the total weight of the
pharmaceutical formulation of the present invention, comprising the above 4
APIs.
The largest maximum diameter of the tablet of the present invention,
comprising the
4 APIs, can be about 27mm or less and the depth can be less than about 12.5mm;
preferably, the largest maximum diameter can be between about 26mm to about
27mm and
the depth can be between about 12.5mm to about lOmm; more preferably, the
largest
maximum diameter can be between about 25mm to about 26mm and the depth can be
between about 12mm to about llmm, most preferably, the largest maximum
diameter can
be about 25mm and the depth can be about llmm.
The hardness of the tablet of the present invention, comprising the 4 APIs,
can be
about 75 Strong-Cobb Units (SCU) to about 20 C, preferably, about 55 SCU to
about 25
SCU, as measured by Electronic D-64291 Darmstadt 100-240V.
By way of example, the tablet of the present invention comprises about 150 mg
to
350mg of tenofovir disoproxil fumarate, about 100mg to 300mg of emtricitabine,
about
75mg to 800mg of darunavir and about 100mg of ritonavir. The amount of
darunavir can be
75mg, 150mg, 300mg, 400mg 600mg, or 800mg (corresponding to the doses of
commercially available of Prezistae). The said darunavir can be darunavir
ethanolate,
hydrate, or any other crystalline form as well as darunavir amorphous. The
amount of
ritonavir can be 100mg of ritonavir (corresponding to the dose of the
commercially
available of Norvir tablet).
Preferably, the tablet of the present invention comprises about 300mg of
tenofovir
disoproxil fumarate, about 200mg of emtricitabine, about 800mg of darunavir
and 100mg of
ritonavir.
In certain embodiments, the tablet of the present invention comprises from
about
20% to about 70% by weight of total weight of the pharmaceutically active
ingredients. The
tablet of the present invention comprises from about 20% to about 85% by
weight of total
weight of all 4 pharmaceutically active ingredients. The pharmaceutical
formulation of the
present invention comprises from about 20% to about 25%, to about 30%, to
about 35%, to
about 40%, to about 45%, to about 50%, to about 55%, to about 60%, to about
65%, to
about 70%, to about 75%, to about 80%, or to about 85% by weight of total
weight of all 4
pharmaceutically active ingredients, or from about 25% to about 30%, to about
35%, to
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about 40%, to about 45%, to about 50%, to about 55%, to about 60%, to about
65%, to
about 70%, to about 75%, to about 80%, or to about 85%, or from about 30% to
about 35%,
to about 40%, to about 45%, to about 50%, to about 55%, to about 60%, to about
65%, to
about 70%, to about 75%, to about 80%, or to about 85%, or from about 40% to
about 45%,
to about 50%, to about 55%, to about 60%, to about 65%, to about 70% , to
about 75%, to
about 80%, or to about 85%, or from about 45% to about 50%, to about 55%, to
about 60%,
to about 65%, to about 70%, to about 75%, to about 80%, or to about 85%, or
from about
50% to about 55%, to about 60%, to about 65%, to about 70%, to about 75%, to
about 80%,
or to about 85% or from about 55%, to about 60%, to about 65%, to about 70%,
to about
75%, to about 80%, or to about 85%, or from about 60% to about 65%, to about
70%, to
about 75%, to about 80%, or to about 85%, or from about 65% to about 70%, to
about 75%,
to about 80%, or to about 85%, or from about 70% to about 75%, to about 80%,
or to about
85%, or from about 75%, to about 80%, or to about 85%, or from about 80% to
about 85%
by weight of all 4 pharmaceutically active ingredients.
According to some embodiments, the present invention provides tablets which
optionally can be divided into two or more discrete segments, for example, by
dividing
grooves. Said dividing grooves facilitate breaking the dosage into the
corresponding
fragments and therefore provide an easy division into partial doses which
contain
approximately equal proportions of the active substances. The tablets of the
present
invention may, for example have one to three, preferably two, laterally
extending grooves
on the top and bottom surfaces and a small laterally opening groove on the
sides, to
facilitate ease in breaking the tablet.
Pharmaceutical formulations in the form of a tablet according to the present
invention can be provided for example as a monolithic tablet (single layer),
bi-layer (two
layers) or multi-layer tablet (three or more distinct layers), preferably the
formulation can be
a monolithic tablet.
A monolithic tablet according to the present invention can include the four
compounds/active pharmaceutical ingredients mixed and compressed to a single
layer
tablet. The single layer can include darunavir with extra- granular ritonavir
or darunavir
with intra- granular ritonavir, (i.e., a granulate of darunavir-ritonavir)
emtricitabine
granules, and tenofovir granules, or granules comprising both emtricitabine
and tenofovir.
To these can be added at least one disintegrant such as Croscarmellose Sodium
(Ac-Di-Sol)
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to form a blend that is then compressed into a tablet core. The tablet core
can then be coated
with a film coating material to produce a film coated tablet.
The granulate of darunavir-ritonavir can be prepared by wet granulation of
darunavir. The wet granulation can include top spray process of at least one
binder such as
hypromellose dissolved in a suitable liquid (e.g., water) on darunavir,
obtaining a wet
granulate followed by drying the wet granulate and milling the dry granulate.
Then at least one lubricant such as sodium stearyl fumarate can be added to
the
obtained mixture to obtain the final blend of darunavir-ritonavir(i.e.,
darunavir with extra-
granular ritonavir).
Alternatively, the granulate of darunavir-ritonavir can be prepared by wet
granulation, at least one binder such as hypromellose dissolved in a suitable
liquid (e.g.
water), can be top spray process on a mixture of darunavir and ritonavir pre-
mix or,
followed by drying the wet granulate and milling the dry granulate. The
obtained granulate
of darunavir and ritonavir, can then be mixed with at least one filler such as
microcrystalline
cellulose, at least one disintegrant such as crospovidone, and at least one
glidant such as
silicon dioxide. Optionally, castor oil can be added to the obtained mixture.
Then at least
one lubricant such as sodium stearyl fumarate can be added to the obtained
mixture to
obtain the final blend of darunavir-ritonavir (i.e., darunavir with intra-
granular ritonavir).
Ritonavir pre-mix can be prepared by mixing ritonavir with at least one
carrier such as
copovidone, optionally also with at least one solubilizer such as sorbitan
laurate and with at
least one glidant such as silica, providing a mixture that is the combined
with a solvent,
such as ethanol to yield a second mixture. The solvent is then removed from
the second
mixture by evaporation techniques such as spray drying. The resulting mixture
may be in
the form of a powder, which may be subjected to a particle size reduction step
(e.g., by
milling, to D(0.1) about 9pm, D(0.5) about 551.1m, D(0.9) about 176 m).
Granules comprising both emtricitabine and tenofovir can be prepared by
combining
both APIs and at least one filler selected from: microcrystalline cellulose,
lactose and/ or
pregelatinized starch and optionally at least one disintegrant such as
croscarmellose sodium
to obtain a powdery mixture that can then combined with water in the wet
granulation
process. The wet granulation process provides wet granules that can then be
dried.
Alternatively emtricitabine and tenofovir can be granulated by the same method
separately
to produce separate emtricitabine and tenofovir granulates.
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Alternatively, emtricitabine granulate can be prepared by combining
emtricitabine
with at least one filler selected from: microcrystalline cellulose,
pregelatinized starch and at
least one disintegrant such as croscarmellose sodium to obtain a powdery
mixture that can
then granulated with water in the wet granulation process. The wet granulation
process
provides wet granules that can then be dried. Tenofovir granulate can be
prepared by
combining Tenofovir with at least one filler selected from: microcrystalline
cellulose and
pregelatinized starch to obtain a powdery mixture that can then granulated
with water in the
wet granulation process. The wet granulation process provides wet granules
that can then be
dried.
A bi-layer tablet comprising emtricitabine, tenofovir, darunavir and ritonavir
according to the present invention is composed of two distinct layers of the
compounds/active pharmaceutical ingredients. For example, the first layer can
have
emtricitabine and tenofovir and the second can have darunavir and ritonavir.
The first layer
may further include at least one lubricant such as magnesium stearate to form
the blend of
the first layer. The blend of the second layer can include the above described
granulate of
darunavir-ritonavir (i.e., darunavir and ritonavir as extra-granular or
darunavir and ritonavir
as intra-granular). Both blends can then be compressed into one tablet core
that has two
distinct layers. The tablet core can then be coated with film coating
material.
A multi-layer tablet according to the present invention is composed of three
or more
distinct layers of the compounds/active pharmaceutical ingredients.
Pharmaceutical formulations in the form of a tablet according to the present
invention 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.
The Pharmaceutical formulations in the form of a tablet according to the
present
invention may be further coated with a coating layer. The coating layer may
comprise, for
example, a protective top coat which is disposed over the drug layer.
According to some
embodiments, the protective top coat layer may comprise a coating polymer and
optionally
one or more excipients such as, for example, a plasticiser, an anti-adherent
or glidant, one or
more pigments/opacifying agents, and combinations thereof
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The coating may be a water-soluble film coating that has no influence on the
release
of the active substance. The thickness of a soluble film coating may be from
about 20 pm to
about 100 m.
Suitable film coating materials include, for example, cellulose derivatives,
such as
cellulose ethers, for example methylcellulose, hydroxypropylcellulose or
hydroxypropylmethylcellulose; mixtures of polyvinyl pyrrolidone or of a
copolymer of
polyvinyl pyrrolidone and polyvinyl acetate with hydroxypropylmethylcellulose;
mixtures
of shellac with hydroxypropylmethylcellulose, polyvinyl acetate or copolymers
thereof with
polyvinyl pyrrolidone; or mixtures of water-soluble cellulose derivatives,
such as
hydroxypropylmethylcellulose, and water-insoluble ethylcellulose. These
coating 'agents
may, if desired, be used in admixture with other adjuncts, such as talc,
wetting agents, for
example polysorbates (for example for facilitating application), or pigments
(for example,
for marking purposes). Depending on the solubility of the constituents, these
coatings can
be applied in aqueous solution or in organic solution (for example, solutions
of shellac or
ethylcellulose in organic solvents). Mixtures of acrylates that are water-
insoluble per se may
also be used. For example, the copolymer of ethyl acrylate and methyl
methacrylate may be
used in an aqueous dispersion, with one or more water-soluble adjuncts, such
as lactose,
polyvinyl pyrrolidine, polyethylene glycol or hydroxypropylmethylcellulose.
Suitable plasticizers for the protective top coat include, for example,
triacetin,
diethyl phthalate, dibutyl sebacate, tributyl sebacate polyethylene glycol,
and mixtures
thereof. Polyethylene glycol is a preferred plasticizer.
Suitable anti-adherent or glidants for the protective top coat include, for
example,
, talc, fumed silica, magnesium stearate, and mixtures thereof.
The tablet of the present invention can be prepared by a process comprising:
(a) Blending a mixture comprising tenofovir disoproxil, emtricitabine,
darunavir,
ritonavir and optionally one or more pharmaceutically acceptable excipients;
(b) Compressing the blend into tablet cores; and
(c) Optionally applying one or more coating layers over the tablet cores.
Preferably, the tablet obtained by this process is a monolithic tablet.
Alternatively, the tablet of the present invention can be prepared by a
process
comprising:
(a) Providing two blend layers, wherein:
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(i) the first layer comprises either a mixture of emtricitabine granulates and
tenofovir granulates, or a granulate comprising a mixture of emtricitabine and
tenofovir;
and
(ii) the second layer comprises darunavir with extra- granular ritonavir or
darunavir with intra- granular ritonavir, (i.e., a granulate of darunavir-
ritonavir);
(b) compressing the two blend layers into a tablet; and
(c) optionally applying one or more coating layers over the tablet cores.
Preferably, the tablet obtained by this process is a bi layer tablet. Blending
can be
accomplished using equipment such as tumble blender.
Compression can be accomplished using for example, the blend of active
ingredients
and excipients is passed through a roller apparatus for compaction. However,
other means
for compacting the API mixture, e.g., compaction into slugs (or "slugging"),
may be used.
Alternatively, the active pharmaceutical ingredients blend of step (a) can be
processed into other unitary dosage forms such as capsules, or the like.
Each of the individual active pharmaceutical ingredients in the mixture in
step (a)
can be processed prior to blending as described above.
Wet granulation can be accomplished using conventional equipment. For example,
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.
Wet milling can be accomplished using conventional equipment. For example, to
facilitate a uniform drying process, each wet granulation can be
deagglomerated with a mill
fitted with a screen and an impeller.
Drying can be accomplished using conventional equipment. For example, milled
wet
granules can be dried using fluid-bed dryer.
Dry milling can be accomplished using conventional equipment. For example, all
dried granules can be milled using a rotary sieve mill.
Top spray process can be accomplished using conventional equipment. For
example
Fluid Bed Dryer equipped with either top spray or vvurster coating devices.
Tablet compression can be accomplished using conventional equipment. For
example, the final blends can be compressed using tabletting machine. Purity
analysis can
be accomplished using conventional equipment. For example HPLC.
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The present invention provides a monolithic tablet comprising:
darunavir or a physiologically functional derivative thereof, and
ritonavir or a physiologically functional derivative thereof.
Preferably, the tablet can be chemically stable.
The total weight of the monolithic tablet comprising Darunavir and Ritonavir
of the present invention can be less than or equal to about 1.300g, less than
or equal to about
1.200g, less than or equal to about 1.100g, less than or equal to about
1.000g, less than or
equal to about 0.900g, less than or equal to about 0.700, less than or equal
to 0.600g, or less
than or equal to about 0.550g. In a specific embodiment of the present
invention the tablet
weight is between 0.550g to about 0.600g, to about 0.700g, to about 0.900g, to
about
1.000g, to about 1.100g, to about 1.200g, to about 1.300g, or between 0.600g
to about
0.700g, to about 0.900g, to about 1.000g, to about 1.100g, to about 1.200g, or
to about
1.300g, or between 0.700g to about 0.900g, to about 1.000g, to about 1.100g,
to about
1.300g, or between0.900g to about 1.000g, to about 1.100g, to about 1.200g, or
to about
1.300g, or between 1.000g to about 1.100g, to about 1.200g, to about 1.300g,
or between
1.100g to about 1.200g, or to about 1.300g, or between 1.200g to about 1.300g.
The monolithic tablet comprising darunavir and ritonavir of the present
invention
provides a chemically stable formulation of the active agents, and moreover,
is suitable for
once daily administration in a single pill. Advantageously, the size and
weight of the
dosage form is far less than the combined size/weight of commercially
available darunavir
800mg tablet (Prezista , having total weight of 1048 mg) and commercially
available
ritonavir 100mg tablet (Norvire, having a total weight of 800mg).
The largest maximum diameter of the pharmaceutical formulation of the present
invention, comprising darunavir and ritonavir, can be about 22mm or less and
the depth can
be less than about 9mm; preferably, the largest maximum diameter can be
between about
20mm to about 22mm and the depth can be between about 6mm to about 9mm; more
preferably, the largest maximum diameter can be between about 20mm to about
21mm and
the depth can be between about 8mm to about 7mm, most preferably, the largest
maximum
diameter can be about 21mm and the depth can be about 7mm.
By way of example, the tablet of the present invention comprises about 150 mg
to
350mg of tenofovir disoproxil fumarate, about 100mg to 300mg of emtricitabine,
about
75mg to 800mg of darunavir and about 100mg of ritonavir. The amount of
darunavir can be
75mg, 150mg, 300mg, 400mg 600mg, or 800mg (corresponding to the doses of
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commercially available of Prezistag). The said darunavir can be darunavir
ethanolate,
hydrate, or any other crystalline form as well as darunavir amorphous. The
amount of
ritonavir can be 100mg of ritonavir (corresponding to the dose of the
commercially
available of Norvirg tablet).
Preferably, the tablet of the present invention comprises about 300mg of
tenofovir
disoproxil fumarate, about 200mg of emtricitabine, about 800mg of darunavir
and 100mg of
ritonavir.
In certain embodiments, the monolithic tablet comprising darunavir and
ritonavir of
the present invention comprises from about 20% to about 85% by weight of total
weight of
the two pharmaceutically active ingredients. The tablet of the present
invention comprises
from about 20% to about 25%, to about 30%, to about 35%, to about 40%, to
about 45%, to
about 50%, to about 55%, to about 60%, to about 65%, to about 70%, to about
75%, to
about 80% or to about 85% by weight of total weight of the two
pharmaceutically active
ingredients, or from about 25% to about 30%, to about 35%, to about 40%, to
about 45%, to
about 50%, to about 55%, to about 60%, to about 65%, to about 70%, to about
75%, to
about 80%, or to about 85%, or from about 30% to about 35%, to about 40%, to
about 45%,
to about 50%, to about 55%, to about 60%, to about 65%, to about 70%, to about
75%, to
about 80%, or to about 85%, or from about 40% to about 45%, to about 50%, to
about 55%,
to about 60%, to about 65%, to about 70% , to about 75%, to about 80%, or to
about 85%,
or from about 45% to about 50%, to about 55%, to about 60%, to about 65%, or
to about
70%, to about 75%, to about 80% or to about 85%, or from about 50% to about
55%, to
about 60%, to about 65%, to about 70%, to about 75%, to about 80%, or to about
85%, or
from about 55%, to about 60%, to about 65% or to about 70%, to about 75%, to
about 80%
or to about 85%, or from about 60% to about 65%, to about 70%, to about 75%,
to about
80%, or to about 85%, or from about 65%, to about 70%, to about 75%, to about
80%, or to
about 85%, or from about 70% to about 75%, to about 80%, or to about 85%, or
form about
75% to about 80% or to about 85%, or from about 80% to about 85% by weight of
the two
pharmaceutically active ingredients.
The above monolithic tablet comprising darunavir and ritonavir can include the
two
= compounds/active pharmaceutical ingredients mixed and compressed to a
single layer
tablet. The single layer can include darunavir and ritonavir as extra-
granular or darunavir
and ritonavir as intra- granular. To these can be added at least one lubricant
such as sodium
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stearyl fumarate to form a blend that can then be compressed into a tablet
core. The tablet
core can then be coated with a film coating material to produce a film coated
tablet.
Darunavir and ritonavir as extra- granular or intra- granular can be processed
prior
to blending as described above.
According to some embodiments, the present invention provides tablets which
optionally can be divided into two or more discrete segments, for example, by
dividing
grooves. Said dividing grooves facilitate breaking the dosage into the
corresponding
fragments and therefore provide an easy division into partial doses which
contain
approximately equal proportions of the active substances. The tablets of the
present
invention may, for example have one to three, preferably two, laterally
extending grooves
on the top and bottom surfaces and a small laterally opening groove on the
sides, to
facilitate ease in breaking the tablet.
The pharmaceutical formulations of the present invention may further comprise
one
or more pharmaceutically acceptable carriers or excipients as described above
and below.
Examples of pharmaceutical excipients are fillers, binders, disintegrants,
surfactants,
glidants and lubricants.
Suitable fillers (diluents) include, for example, water soluble polymer, water
insoluble polymer, microcrystalline cellulose (for example, Avicel PH102
having or
PH101), lactose in its various forms (e.g., lactose USP, anhydrous or spray
dried), sorbitol,
dextrose, sucrose, mannitol, xylitol, maltose, polyols, fructose, guar gum,
magnesium
hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch,
and the
like or any combinations thereof.
Suitable binders include, for example, cellulose polymers (e.g., hydroxypropyl-
methyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl
cellulose),
polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch and
the like or any
combinations thereof
Suitable lubricants include, for example, sodium stearyl fumarate, stearic
acid,
magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl behenate
or hydrogenated
vegetable oils, and the like or any combinations thereof
Suitable glidants can be used to improve the flowability. Suitable glidants
include,
for example, colloidal silica, silica gel, precipitated silica or talc, and
the like or any
combinations thereof
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Suitable disintegrants include, for example, sodium carboxymethyl starch,
cross-
linked polyvinylpyrrolidone (Crospovidone), sodium carboxymethyl glycolate
(for example
Explotab ), croscarmellose sodium, swelling polysaccharide, for example soy
polysaccharide, carrageenan, agar, pectin, starch and derivatives thereof,
protein, for
example formaldehyde-casein, sodium bicarbonate, ion exchange resin and the
like or any
combinations thereof.
Suitable surfactants al re substances, which can lower the interfacial tension
between
two phases, thus enabling or supporting the formation of dispersions or
working as a
solubilizer. Suitable surfactants include, for example, alkyl sulfates (for
example sodium
lauryl sulfate), alkyltrimethylammonium salts, alcohol ethoxylates, sorbitanes
(for example
sorbitan laurate), polyoxyethylene sorbitanes, polyoxylglycerides, or
polyoxyethylene
castor oil derivatives. Sorbitan laurate and sodium lauryl sulfate are
preferred surfactants.
The above disclosed unit dose formulation of the 4 APIs or the above
monolithic
tablet of the 2 APIs can be used as a medicament. In particular, the
formulations of the
present invention can also be used in the treatment of HIV-1 infection.
The present invention further provides a method for treating HIV-1 infection
comprising administration of a pharmaceutically effective amount of the above
unit dose
formulation of the 4 APIs or of the above monolithic tablet of the 2 APIs.
The present invention is illustrated by the following examples, which are not
intended to limit the scope of the invention. It will be appreciated that
various
modifications are within the spirit and scope of the invention.
ANALYTICAL METHOD
Assay Analytical method for tablet comprising darunavir and ritonavir
Chromatographic System
Column & Packing: Phenomenex Luna C18(2) 5[tm,100A
250x4.6mm
Column Temperature: 30
Mobile Phase: Buffer sol. (pH 3.2):Acetonitrile (40:60)
Flow Rate: 1.0 mL/min.
Detector: UV at 240 nm, 10 mm flow cell path length
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Analytical method for tablet comprising emtricitabine, tenofovir, darunavir,
ritonavir:
Impurities and Degradants Determination Chromatographic conditions for
emtricitabine/tenofovir/darunavir:
Column: Inertsil ODS-3, 150x4.6mm, 3um
Column temperature: 40 C
Mobile phase:
Sol. A: Acetate buff. pH 4.6:Me0H (95:5 v/v)
Sol. B: acetonitrile (ACN)
By gradient:
Flow: 0.8mL/min
Detector: UV at 262nm (by PDA),
lOmm flow cell path length
Gradient
Assay Chromatographic conditions:
Time SoLA SUB
Column: Phenomenex Luna C18(2), 250x4.6mm, 5um
0 99.0 1.0
Column temperature: 30 C
95.0 5.0
Mobile phase:
Sol. A: H20 (pH 3.2):ACN (90:10 v/v) 15 90.0 10.0
Sol. B: ACN 59 29.0 71.0
60 1.0 99.0
By gradient:
62 1.0 99.0
Detector: UV at 240nm, lOmm flow cell path length
62.1 99.0 1.0
Impurities and Degradants Determination 68 99.0 1.0
Chromatographic conditions for Ritonavir.
Column: ACQUITY UPLC BEH C8 1.7um, 2.1x100mm
Column temperature: 50 C
Mobile phase:
Sol. A = Buffer: tetrahydrofuran (THF):n-Butanol (87:8:5 v/v)
Sol. B = ACN:THF:n-Butanol (87:8:5 v/v)
By gradient:
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Gradient
Flow: 0.6mL/min
Time SoLA SoLB
Detector: UV at 240run (by PDA),
0 85 15
lOmm flow cell path length
75 25
12 75 25
30 70
16 30 70
16.1 85 15
85 15
EXAMPLES
Example 1: Preparation of ritonavir pre-mix
Ingredient mg/tablet
Ritonavir 100.00
Copovidone 20.00
Sorbitan laurate 7.00
Colloidal silica, anhydrous 3.00
Pre-mix total: 130.00
Ritonavir and the excipients were dissolved in ethanol. Ethanol was evaporated
to
obtain dry powder. The powder was then milled to lower particle size
Example 2: Preparation of a monolithic tablet containing darunavir ¨ ritonavir
extra-
granular
Raw Material Mg/tablet
Darunavir Hydrate 865.75
Hypromellose (Methocel E-15) 12.20
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microcrystalline cellulose (Avicel 101) 14.00
Ex-Granular (Part I)
microcrystalline cellulose (Avicel 102) 150.26
Crospovidone LX 30.50
Silicon di-oxide (Aerosil) 3.04
Ritonavir Pre mix (example 1) 130.00
Ex-Granular (Part II)
Sodium Stearyl Fumarate 12.00
Total Tablet weight 1217.75
Darunavir granulation- darunavir was wet granulated by a top spray process
using
hypromellose (Methocel E-15) as granulation solution and purified water as
granulation
liquid.
The wet granulated material was then dried in Fluid bed drier and milled to
lower
particle size.
Darunavir granulate, ritonavir pre mix (prepared according to example 1),
crospovidone, microcrystalline cellulose (Avicel 102) and Silicon di-oxide
(Aerosil) -were
mixed and then sodium stearyl fumarate was added for final mixing, and the
mixture was
further compressed into tablet cores.
The tablet cores were then coated with a film coating material to produce film
coated tablets. (Approximately 3% weight gain).
Example 3: Preparation of a monolithic tablet containing darunavir - ritonavir
(intra-
granular)
Raw Material mg/tablet
Darunavir Hydrate 865.75
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Hypromellose (Methocel E-15) 12.20
Ritonavir Pre mix (example 1) 130.00
Ex-Granular (Part I)
microcrystalline cellulose (Avicel 102) 164.26
Crospovidone LX 30.50
Silicon di-oxide (Aerosil) 3.05
Ex-Granular (Part II)
Sodium stearyl fumarate 12.00
Total Tablet weight 1217.76
Darunavir ¨ Ritonavir granulation- darunavir was wet granulated with ritonavir
pre
mix (prepared according to example 1) by a top spray process using
hypromellose
(Methocel E-15) as granulation solution and purified water as granulation
liquid.
The wet granulated material was then dried in Fluid bed drier and milled to
lower
particle size.
Darunavir ¨ ritonavir granulate, crospovidone, microcrystalline cellulose
(Avicel
102) and Silicon di-oxide (Aerosil) were mixed and then sodium stearyl
fumarate was
added for final mixing, and the mixture was further compressed into tablet
cores.
The tablet cores were then coated with a film coating material to produce film
coated tablets. (Approximately 3% weight gain).
Example 4: Preparation of emtricitabine/ tenofovir granulate
Raw Material A
mg/tablet mg/tablet
Emtricitabine 200 200
Tenofovir disoproxil fumarate 300 300
microcrystalline cellulose 90.30 90.30
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(Avicel 102)
Lactose monohydrate 48.10 48.10
Pregelatinized starch 1500 30.09 30.09
Croscarmellose Sodium (Ac-Di- 3.51 3.51
Sol)
Ex-Granular (Part I)
Croscarmellose Sodium (Ac-Di- 28.0
Sol)
Val eig t '17-0-010-0 67-7.60
Emtricitabine/ tenofovir disoproxil fumarate were wet granulated by High Shear
Mixer with microcrystalline cellulose (Avicel 102), Lactose monohydrate,
Pregelatinized
Starch and Croscarmellose Sodium (Ac-Di-Sol). The granules were then dried by
Fluid Bed
Drier and milled to lower particle size [see above comments]. Optionally,
croscarmellose
Sodium was then added as an extra-granular disintegrant.
Example 5: Preparation of emtricitabine granulate
Ingredient mg/tablet
Emtricitabine 200.00
Mannitol 50.00
Lactose monohydrate 90.00
Crospovidone 30.00
Povidone 10.00
Emtricitabine granulate total: 380.00
Emtrcitabine is mixed with excipients and wet granulated using povidone
solution in
purified water. The wet granulate is then dried in a fluid bed dryer.
Example 5A: Preparation of emtricitabine granulate
Ingredient mg/tablet
Emtricitabine 200.00
Microcrystalline cellulose 25.00
(Avicel pH 101)
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Croscarmellose Sodium (Ac- 25.00
Di-Sol)
Pregelatinized starch 1500 50.00
Emtricitabine granulate total: 350.00
Emtrcitabine was mixed with excipients and wet granulated using povidone
solution
in purified water. The wet granulate was then dried in a fluid bed dryer.
Example 6: Preparation of tenofovir Disoproxil Fumarate granulate
Ingredient mg/tablet
Tenofovir Disoproxil 300.00
Fumarate
Microcrystalline cellulose 130.00
(Avicel PH 101)
Lactose monohydrate 100.00
Pregelatinized starch 50.00
Tenofovir granulate total: 580.00
Tenofovir Disoproxil Fumarate was mixed with excipients and wet granulated
using
purified water. The wet granulate was then dried in a fluid bed dryer.
Example 7: Preparation of tenofovir disoproxil fumarate granulate by dry
mixing
Ingredient mg/tablet
Tenofovir disoproxil fumarate 300.00
Mannitol 45.00
Lactose monohydrate 144.00
Crospovidone 36.00
Total weight: 525.00
Tenofovir granulation is produced by dry mixing of tenofovir Disoproxil
together
with the excipients.
Example 7A: Preparation of Tenofovir Disoproxil Fumarate granulate
Ingredient mg/tablet
Tenofovir Disoproxil 300.00
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Fumarate
Microcrystalline cellulose 230.00
(Avicel PH 101)
Pregelatinized starch 50.00
Tenofovir granulate total: 580.00
Tenofovir Disoproxil Fumarate was mixed with excipients and wet granulated
using
purified water. The wet granulate was then dried in a fluid bed dryer.
Example 8: preparation of a monolithic tablet containing emtricitabine,
tenofovir,
darunavir and ritonavir (extra-granular).
Raw Material mg/tablet mg/tablet
A
Emtricitabine/ Tenofovir 700.00 672.00
disoproxil fumarate Granulate
including the extra-granular
disintegrant, prepared according
to example 4A or 4B
Darunavir ¨ Ritonavir extra- 1217.75 1217.75
granular, prepared according to
example 2, excluding the
compression step.
w eiiht '1 17 - 11889.75 ,
Emtricitabine/ tenofovir granulate including the extra-granular disintegrant,
was
prepared according to example 4A or 4B. Then darunavir-ritonavir formulations,
prepared
according to example 2, were added. Then, the final mixture was further
compressed into
tablet cores.
The tablet cores were then coated with a film coating material to produce film
coated tablets. (Approximately 3% weight gain).
Example 9: Preparation of a bi-layer tablet containing emtricitabine and
tenofovir in
the first layer, darunavir and ritonavir (extra-granular) in the second layer.
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Raw Material mg/tablet
Emtricitabine/ Tenofovir 700.00
Disoproxil fumarate
Granulate including the
extra-granular disintegrant,
prepared according to
example 4A
Magnesium stearate 7.00
Darunavir ¨ Ritonavir extra- 1217.75
granular, prepared according
to example 2, excluding the
compression step.
eta' weigh I *E147-5
Final blend 1st layer:
Emtricitabine/ tenofovir granulate including the extra-granular disintegrant
is
prepared according to example 4A, then it is mixed with Magnesium stearate.
Final blend 2nd layer:
Darunavir-ritonavir formulation, prepared according to example 2, excluding
the
compression step.
The two blends are then compressed into tablet cores.
The tablet cores are then coated with a film coating material to produce film
coated
tablets. (Approximately 3% weight gain).
Example 10: Preparation of a monolithic tablet containing emtricitabine,
tenofovir,
darunavir and ritonavir (intra-granular).
Raw Material mg/tablet mg/tablet
Emtricitabine/ Tenofovir 700.00 672.00
Disoproxil fumarate Granulate
including the extra-granular
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disintegrant addition, prepared
according to example 4A or 4B.
Darunavir ¨ Ritonavir intra- 1217.76 1217.76
granular, prepared according to
example 3, excluding the
compression step
'rimy weight Wall 813: .76
Emtricitabine/ tenofovir granulate including the extra-granular disintegrant,
was
prepared according to example 4A or 4B. Then darunavir-ritonavir formulation,
prepared
according to example 3 was added, excluding the compression step. Then, the
final mixing
was further compressed into tablet cores.
The tablet cores were then coated with a film coating material to produce film
coated tablets. (Approximately 3% weight gain).
Example 11: Preparation of a bi-layer tablet containing emtricitabine and
tenofovir in
the first layer, darunayir and ritonavir (intra-granular) in the second layer.
Raw Material mg/tablet
Emtricitabine/ Tenofovir 700.00
Disoproxil fumarate
Granulate, prepared
according to example 4A
Magnesium stearate 7.00
Darunavir ¨ Ritonavir intra- 1217.76
granular, prepared according
to example 3, excluding the
compression step
ot
aleilit 1i24
Final blend 1st layer:
Emtricitabine/ tenofovir granulate including the extra-granular disintegrant,
is
prepared according to example 4A, then it is mixed with magnesium stearate.
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Final blend 2" layer:
Darunavir-ritonavir formulation, prepared according to example 3, excluding
the
compression step.
The two blends are then compressed into tablet cores.
The tablet cores are then coated with a film coating material to produce film
coated
tablets. (Approximately 3% weight gain).
