Note: Descriptions are shown in the official language in which they were submitted.
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STABLE DOSAGE FORMS OF ARTEROLANE AND PIPERAQUINE
Field of the Invention
The field of the invention relates to stable oral dosage forms comprising
spiro or
dispiro 1,2,4-trioxolane antimalarials, or their pharmaceutically acceptable
salts, prodrugs
and analogues and processes for their preparation.
Background of the Invention
Malaria, the most common parasitic disease of humans, remains a major health
and
economic burden in most tropical countries. Large areas of Central and South
America,
Hispaniola (Haiti and the Dominican Republic), Africa, the Middle East, the
Indian
subcontinent, Southeast Asia, and Oceania are considered as malaria-risk
areas. It leads to
a heavy toll of illness and death, especially amongst children and pregnant
women.
According to the World Health Organization, it is estimated that the disease
infects about
400 million people each year, and around two to three million people die from
malaria
every year. There are four kinds of malaria parasites that infect human:
Plasmodium
falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae.
Malaria spreads from one person to another by the bite of mosquito, Anopheles
gambiae, which serves as vector. When a mosquito sucks the blood of human,
sporozoites
are transfused into the human body together with saliva of the mosquito. The
sporozoites
enter into the hepatocytes, reproduce asexually and fmally enter into the
blood stream. The
parasites continue to multiply inside the red blood cells, until they burst
and release large
number of merozoites. This process continues, destroying a significant number
of blood
cells and causing the characteristic paroxysm ("chills and fever") associated
with the
disease. In the red blood cells, some of the merozoites become male or female
gametocytes. These gametocytes are ingested by the mosquito when it feeds on
blood. The
gametocytes fuse in the vector's gut; sporozoites are produced and are
migrated to the
vector's salivary glands.
The clinical symptoms of malaria are generally associated with the bursting of
red
blood cells causing an intense fever associated with chills that can leave the
infected
individual exhausted and bedridden. More severe symptoms associated with
repeat
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infections and/or infection by Plasmodium falciparum include anaemia, severe
headaches,
convulsions, delirium and, in some instances, death.
Quinine, an antimalarial compound that is extracted from the bark of cinchona
tree,
is one of the oldest and most effective drugs in existence. Chloroquine and
mefloquine are
the synthetic analogs of quinine developed in 1940's, which due to their
effectiveness, ease
of manufacture, and general lack of side effects, became the drugs of choice.
The
downside to quinine and its derivatives is that they are short-acting and have
bitter taste.
Further, they fail to prevent disease relapses and are also associated with
side effects
commonly known as "Chinchonism syndrome" characterized by nausea, vomiting,
dizziness, vertigo and deafness. However, in recent years, with the emergence
of drug-
resistant strains of parasite and insecticide-resistant strains of vector, the
treatment and/or
control of malaria is becoming difficult with these conventional drugs.
Malarial treatment further progressed with the discovery of Artemisinin
(qinghaosu), a naturally occurring endoperoxide sesquiterpene lactone isolated
from the
plant Artemisia annua (Meshnick et al., Microbiol. Rev. 1996, 60, p. 301-315;
Vroman et
al., Curr. Pharm. Design, 1999, 5, p. 101-138; Dhingra etal., 2000, 66, p. 279-
300), and a
number of its precursors, metabolites and semi-synthetic derivatives which
have shown to
possess antimalarial properties. The antimalarial action of artemisinin is due
to its reaction
with iron in free heme molecules of the malaria parasite, with the generation
of free
radicals leading to cellular destruction. This initiated a substantial effort
to elucidate its
molecular mechanism of action (Jefford, dv. Drug Res. 1997, 29, p. 271-325;
Cumming et
al., Adv. Pharmacol. 1997, 37, p. 254-297) and to identify novel antimalarial
peroxides
(Dong and Vennerstrom, Expert Opin. Ther. Patents 2001, 11, p. 1753-1760).
Although the clinically useful artemisinin derivatives are rapid acting and
potent
antimalarial drugs, they have several disadvantages including recrudescence,
neurotoxicity, (Wesche et al., Antimicrob. Agents. Chemother. 1994, 38, p.
1813-1819)
and metabolic instability (White, Trans. R. Soc. Trop. Med. Hyg., 1994, 88, p.
41-43). A
fair number of these compounds are quite active in vitro, but most suffer from
low oral
activity (White, Trans. R. Soc. Trop. Med. Hyg., 1994, 88, p. 41-43 and van
Agtmael et
al., Trends Pharmacol. Sci., 1999, 20, p. 199-205).
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Further all these artemisinin derivatives are conventionally obtained from
plant
source and are therefore expensive. As the cultivation of the plant material
is dependent on
many factors including the weather conditions, the supply source thus becomes
finite and
there are chances of varying yield and potency. This leads to quality
inconsistencies and
supply constraints. As malaria is more prevalent in developing countries, a
switch to
cheaper and effective medicine is highly desirable.
Thus there exists a need in the art to identify new peroxide antimalarial
agents,
especially those which are not dependent on plant source and can be easily
synthesized,
are devoid of ncurotoxicity, and which possess improved solubility, stability
and
pharmacokinetic properties.
Following that, many synthetic antimalarial 1,2,4-trioxanes (Jefford, Adv.
Drug
Res. 1997, 29, p. 271-325; Cumming etal., Adv. Phannacol. 1997, 37, p. 254-
297),
1,2,4,5-tetraoxanes (Vennerstrom et al., J. Med. Chem., 2000, 43, p. 2753-
2758), and other
endoperoxides have been prepared. Various patents/applications disclose means
and
method for treating malaria using Spiro or dispiro 1,2,4-trioxolanes for
example, U.S.
Patent Application No. 2004/0186168 and U.S. Patent Nos. 6,486,199 and
6,825,230. The
present invention relates to solid dosage forms of the various spiro or
dispiro
trioxolanes antimalarial compounds disclosed in these patents/applications and
are
incorporated herein by reference.
Active compounds representing various Spiro and dispiro 1,2,4-trioxolane
derivatives possess excellent potency, efficacy against Plasmodium parasites,
and a lower
degree of neurotoxicity, in addition to their structural simplicity and ease
of synthesis.
Furthermore, these compounds have half-lives which are believed to permit
short-term
treatment regimens comparing favorably to other artemisinin-like drugs. In
general, the
therapeutic dose of trioxolane derivative may range between about 0.1-1000
mg/kg/day, in
particular between about 1-100 mg/kg/day. The foregoing dose may be
administered as a
single dose or may be divided into multiple doses. For malaria prevention, a
typical dosing
schedule could be, for example, 2.0-1000 mg/kg weekly beginning 1-2 weeks
prior to
malaria exposure, continued up to 1-2 weeks post-exposure.
Monotherapy with artemisinin (natural or synthetic) class of drugs might cure
the
patients within 3 days, however perceiving the potential threat of the
malarial parasite
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developing resistance towards otherwise very potent artemisinin class of
drugs, WHO had
strictly called for an immediate halt to the provision of single-drug
artemisinin malaria
pills. Combination therapy in case of malaria retards the development of
resistance,
improve efficacy by lowering recrudescence rate, provides synergistic effect,
and increase
exposure of the parasite to the drugs.
Artemsinin based combinations are available in the market for a long time.
Artemether-lumafentrine (Co-artem ) was the first fixed dose antimalarial
combination
containing an artemisinin derivative and has been known since 1999. This
combination
has passed extensive safety and efficacy trials and has been approved by more
than 70
regulatory agencies. Co-artem is recommended by WHO as the first line
treatment for
uncomplicated malaria.
Other artemisinin based combinations include artesunate and amodiaquine
(Coarsucamt), and dihydroartemisin and piperaquine (Eurartesim ).
Unfortunately, all
the available artemisinin based combinations have complicated dosage regimens
making it
difficult and inconvenient for a patient to comply completely with the total
prescribed
duration. For example, the dosage regimen of Co-artem for an adult having
body weight
of more than 35 kg includes 6 doses over three days. The first dose comprises
four tablets
initially, the second dose comprises four tablets after eight hours, the third
to sixth doses
comprise four tablets twice for another two days; making it a total of 24
tablets. The
dosage regimen of Coarsucam for an adult having body weight of more than 36
kg or
age above 14 years includes three doses over three days; each dose comprises
two tablets;
making it a total of six tablets. The dosage regimen of Eurartesimt for an
adult having
body weight between 36 kg - 75 kg includes 3 doses over three days, each dose
comprises
of three tablets, making it a total of nine tablets.
It is evident that the available artemisinin-based combinations have a high
pill
burden on patients as they need to consume too many tablets. As noted above,
this may
increase the possibility of missing a few doses, and, consequently, could
result in reduced
efficacy due to non-compliance and may even lead to development of resistance
for the
drug.
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Therefore, there is an urgent and unmet need for anti-malarial combinations
with a
simplified daily dosing regimen that reduces the pill burden and would
increase patient
compliance.
Apart from simplifying the regimen, there are certain limitations for
formulators
5 developing formulations with trioxolones, the first being their
susceptibility to degradation
in presence of moisture that results in reduced shelf lives. Another is their
bitter taste,
which can result in poor compliance of the regimen or selection of another,
possibly less
effective, therapeutic agent.
We have now discovered that a stable antimalarial oral solid dosage form
comprising spiro or dispiro 1,2,4-trioxolanes can be prepared by controlling
the water
content below a certain critical limit. Further, the bitter taste can be
masked by applying a
film coating layer to the solid dosage form.
Summary of the Invention
In one general aspect there is provided a stable solid oral dosage form that
includes
a therapeutically effective amount of a compound having the structural Formula
I,
Formula 1
and its enantiomers, diastereomers, polymorphs, pharmaceutically acceptable
salts and
pharmaceutically acceptable solvates, wherein:
R1 and R2 are same or different and are selected from hydrogen, substituted or
unsubstituted linear or branched alkyl, aryl, and alkaryl groups and
substituted or
unsubstituted alicyclic groups that are optionally interrupted by one or more
oxygen,
sulfur or nitrogen atoms, substituted or unsubstituted aromatic or
heterocyclic groups that
may be interrupted by one or more oxygen, sulfur or nitrogen atoms, a hydroxy
group, and
a halogen, and further providing that the spirocyclohexyl rings attaching RI
and R2 are
optionally interrupted by one or more oxygen, sulfur, or nitrogen atoms; and
one or more
pharmaceutically acceptable excipients, wherein not more than 5% w/w total
related
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substances are formed on storage at 40 C 2 C and 75% 5% relative humidity
over a
period of 6 months.
Embodiments of the solid oral dosage form may include one or more of the
following features. For example, the dosage form may include one or more of
other
antimalarial drugs. The other antimalarial drugs may include quinine,
mefloquine,
lumefantrine, sulfadoxine-pyrimethamine, dihydroartimisinin, piperaquine,
chloroquine,
amodiaquine, proguanil, atovaquone, chloroproguanil, dapsone, fosmidomycin,
tetracycline, DB 289 (pafuramidine maleate), clindamycin, or their salts and
derivatives
thereof. In particular, piperaquine, lumefantrine and DB 289 may be used.
In another general aspect, there is provided a method of treatment of malaria.
The
method includes administering a solid dosage form that includes a
therapeutically effective
amount of a compound of structural Formula I; and one or more pharmaceutically
acceptable excipients, wherein not more than 5% w/w total related substances
are formed
on storage at 40 C 2 C and 75% 5% relative humidity over a period of 6
months.
In another aspect, there is provided a method of treatment of malaria, wherein
the
method includes administering a solid dosage form that includes a
therapeutically effective
amount of a compound of structural Formula I, formulated using a dry or non-
aqueous
process.
In another aspect, there is provided a stable solid oral dosage form, wherein
the
dosage form includes a therapeutically effective amount of a compound of
structural
Formula I; at least one other antimalarial drug selected from lumefantrine,
piperaquine, or
DB 289; and one or more pharmaceutically acceptable excipients.
Embodiments of the oral dosage form may include one or more of the following
features. For example, the water content of the dosage form may not be more
than 6.5%
w/w.
In another general aspect, there is provided a stable oral solid dosage form
comprising cis-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methylpropyl)
aminoicarbony1]-
methyl]-1',2',4'-trioxaspiro[4.5]decane hydrogen maleate; piperaquine; and one
or more
pharmaceutically acceptable excipients.
In another general aspect, there is provided a stable solid oral dosage form
comprising;
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(a) cis-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-
methylpropyl)amino]carbony1]-methyl]-1',2',4'-trioxaspiro[4.5]decane hydrogen
maleate (Active compound I);
(b) piperaquine; and
(c) one or more pharmaceutically acceptable excipients
wherein the dosage form is prepared by a dry process.
In another general aspect, there is provided a stable solid oral dosage form
comprising;
(a) Active compound I; and
(b) piperaquine
wherein the total drug content is within the range of from about 25% to about
85% w/w
based on the total weight of the dosage form.
In another general aspect, there is provided a stable solid oral dosage form
comprising;
(a) Active compound I in an amount of from about 5% to about 25%; and
(b) piperaquine in an amount of from about 40% to about 80%, w/w based on
the total weight of the dosage form.
In another general aspect, there is provided a stable solid oral dosage
comprising;
(a) Active compound I in an amount of from about 5% to about 25%; and
(b) piperaquine in an amount of from about 40% to about 80%
wherein the total drug content does not exceed 85% w/w based on the total
weight of the
dosage form.
In another general aspect, there is provided a stable solid oral dosage of
Active
compound I and piperaquine; wherein the dosage form has dissolution
performance such
that more than 70% w/w of the Active compound I dissolves within 45 minutes,
in a pH
4.5 acetate buffer with 2% tween 80, in USP type II apparatus.
In another general aspect, there is provided a stable solid oral dosage form
comprising;
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(a) Active compound I and
(b) piperaquine; in a weight ratio of about 1:1 to about 1:10.
In another general aspect, there is provided a stable oral solid dosage form
comprising Active compound I present in a dose range of about 100 to about 300
mg and
piperaquine present in a dose range of about 700 mg to about 850 mg.
In another general aspect, there is provided a stable solid oral dosage form
comprising;
(a) Active compound I in an amount of from about 5% to about 25%;
(b) piperaquine in an amount of from about 40% to about 80%;
(c) diluent in an amount of from about 10% to about 40%;
(d) disintegrant in an amount of from about 1% to about 10%; and
(e) lubricant in an amount of from about 1% to about 5%; w/w based on the
total weight of the dosage form.
In another general aspect, there is provided a stable solid oral dosage form
comprising;
(a) Active compound I;
(b) piperaquine;
(c) microcrystalline cellulose;
(d) crospovidone; and
(e) magnesium stearate.
In another general aspect there is provided a stable oral solid dosage
comprising;
(a) Active compound I in an amount of from about 5% to about 25%;
(b) piperaquine in an amount of from about 40% to about 80%; and
(c) microcrystalline cellulose in an amount of from about 10% to about 40%;
w/w based on the total weight of the dosage form.
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In another general aspect, there is provided a stable solid oral dosage form
comprising Active compound I and microcrystalline cellulose in a weight ratio
of about
1:1 to about 1:5.
The pharmaceutically acceptable excipients may be selected from the group
consisting of binders, diluents, glidants/lubric ants, disintegrants,
surfactants and coloring
agents.
The solid dosage form may be in the form of a tablet, capsule, pellet, pill,
granule
or powder. Particularly the dosage form is a tablet or a capsule. More
particularly, the
dosage form is a tablet.
In another general aspect, there is provided a stable solid oral dosage form,
wherein the dosage form is processed and stored at a temperature below 27 C
and relative
humidity 50%.
Embodiments of the process may include one or more of the following features.
For example, the dosage form is formulated using a dry or non-aqueous process.
The non-
aqueous process may include a non-aqueous granulating liquid selected from
ethanol,
isopropyl alcohol, acetone, or dichloromethane for preparing the binder
solution. The dry
process may include direct compression or dry granulation. Dry granulation may
be
compaction or slugging. In particular, the dry granulation may be compaction
for example,
dry roller compaction.
In another general aspect, there is provided a process for the preparation of
a stable
solid oral dosage form, comprising the steps of;
(a) blending Active compound I, piperaquine, and one or more intragranular
excipients;
(b) milling, grinding or sieving the blend by roller compaction to form
granules;
(c) blending the granules with one or more extragranular excipients;
(d) compressing the blend into tablets or filling into capsules.
In another general aspect, there is provided a process for the preparation of
a stable
solid oral dosage form, comprising the steps of;
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(a) blending Active compound I, piperaquine, and one or more
intragranular
excipients;
(b) granulating the blend by slugging;
(c) blending the granules with one or more extragranular excipients;
5 (d) compressing the blend into tablets or filling into capsules.
In another general aspect, there is provided a process for the preparation of
a stable
solid oral dosage form, comprising the steps of;
(a) blending Active compound I, piperaquine, and one or more
pharmaceutically acceptable excipients; and
10 (b) directly compressing the blend into tablets or filling into
capsules.
In another general aspect, there is provided a process for the preparation of
a stable
solid oral dosage form, comprising the steps of;
(a) granulating a blend of one or more excipients;
(b) drying the excipient granules;
(c) blending excipient granules with Active compound I and piperaquine; and
(d) compressing the blend into tablets or filling into capsules.
The tablet may be coated with layer(s) of one or more film forming polymers.
In another general aspect, there is provided a method of treatment of malaria.
The
method includes administering a stable oral solid dosage form comprising;
(a) Active compound I;
(b) piperaquine; and
(c) one or more pharmaceutically acceptable excipients
wherein the dosage form is prepared by a dry process.
In another general aspect, there is provided a stable solid oral dosage form
comprising;
(a) 150 mg of Active compound I and
(b) 750 mg of piperaquine
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wherein the dosage form is administered once a day for three days.
In another general aspect, there is provided a method of treating malaria
comprising administering a stable solid oral dosage form comprising;
(a) 150 mg Active compound I and
(b) 750 mg of piperaquinc
wherein the dosage form is administered once a day for three days.
The details of one or more embodiments are set forth in the description below.
Other features, objects and advantages of the invention will be apparent from
the
description and claims.
Detailed Description of the Invention
We have now discovered that stable solid oral dosage forms of Spiro or dispiro
I ,2,4-trioxolane antimalarials can be prepared which do not degrade
significantly and
provide acceptable shelf life.
The term "stable" as used herein refers to chemical stability of active
compound in
solid dosage forms against decomposition occurring during shelf life due to
hydrolysis,
wherein not more than 5% w/w total related substances are formed on storage at
40 C
2 C and 75% 5% relative humidity over a period of 6 months.
The present invention provides stable solid oral dosage forms of the active
compound, by using excipients having low water content and manufactured using
dry or
non-aqueous formulation processes.
The term "active compound" as used herein includes spiro or dispiro 1,2,4-
trioxolane compound of structural Formula I
'
R2
Formula I
wherein R1 and R2 are same or different and are selected from hydrogen,
substituted or
unsubstituted linear or branched alkyl, aryl, and alkaryl groups and
substituted or
unsubstituted alicyclic groups that are optionally interrupted by one or more
oxygen,
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sulfur or nitrogen atoms, substituted or unsubstituted aromatic or
heterocyclic groups that
may be interrupted by one or more oxygen, sulfur or nitrogen atoms, a hydroxy
group, and
a halogen, and further providing that the spirocyclohexyl rings attaching R1
and R2 are
optionally interrupted by one or more oxygen, sulfur, or nitrogen atoms. In
particular, it
includes compounds of Formula I, wherein Riis hydrogen, for example, compounds
of
structural Formula II.
' x ___
"C)1
0 IFI
N H3C
\*CH3
N--1-1
,
H
Formula II
Active compound includes one or more of the various Spiro and dispiro
trioxolane
derivatives disclosed in U.S. Application No. 2004/0186168 and U.S. Patent
Nos.
6,486,199 and 6,825,230, which are incorporated herein by reference. These
trioxolanes
are relatively sterically hindered on at least one side of the trioxolane
heterocycle which
provides better in vivo activity, especially with respect to oral
administration. Particularly,
Spiro and dispiro 1,2,4-trioxolanes derivatives possess excellent potency and
efficacy
against Plasmodium parasites, and a lower degree of neurotoxicity.
The term "Active compound I" herein means cis-adamantane-2-spiro-3'-8'-[[[(2'-
amino-2'-methylpropypamino]carbonyThmethyl]-1',2',4'-trioxaspiro[4.5]decane
hydrogen
maleate. The Active compound I may be present in an amount of from about 5% to
about
25%, w/w based on the total dosage form.
Further, perceiving the potential threat of the malarial parasite developing
resistance towards otherwise very potent artemisinin class of drugs, WHO has
called for
an immediate halt to the provision of single-drug artemisinin malaria pills.
In the case of
malaria, combination therapy has been applied since around 1990. However, this
strategy
is being hampered because the Plasmodium parasite has developed resistance, as
a result
of monotherapy, to certain components of currently applied combination drugs.
Combination therapy is expected to retard the development of resistance,
improve efficacy
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by lowering recrudescence rate, provide synergistic effect, and increase
exposure of the
parasite to the drugs.
Embodiments of the solid oral dosage of the present invention further include
one
or more of antimalarial drugs. The antimalarial drugs may include quinine,
mefloquine,
lumefantrine, sulfadoxine-pyrimethamine, dihydroartimisinin, piperaquine,
chloroquine,
amodiaquine, proguanil, atovaquone, chloroproguanil, dapsone, fosmidomycin,
tetracycline, DB 289 (pafuramidine maleate), clindamycin, or their salts and
derivatives
thereof. In particular, piperaquine, lumcfantrine and DB 289 may be used;
however
piperaquine remains the preferred one.
Selection of combination as an antimalarial therapy is based on certain
attributes.
Synthetic artemisinin derivatives exhibit their action by their reaction with
the iron in free
heme molecules in the malaria parasite with the generation of free radicals
leading to
cellular destruction. On the other hand bisquinoline derivatives such as
piperaquine
interfere with the detoxification of haemin in the digestive vacuole of the
parasite to non-
toxic malaria pigment, so that haemin can generate free radicals and membrane
damage
follows. The unrelated mode of action of the two drugs would provide improved
therapy,
and treatment against all stages of parasites including gametocytes.
Additionally, since
synthetic artemisinin derivatives are very efficacious and highly potent,
these would
thereby treat the symptoms quickly, exhibiting fast recovery rates. The
combination of
synthetic artemisinin derivatives and bisquinoline derivatives such as
piperaquine provide
a short duration of treatment.
Piperaquine is a bisquinoline compound that has antimalarial activity against
both
P. vivax and P. falciparum, including strains of chloroquine resistant P.
falciparum. The
tolerability, efficacy, pharmacokinetic profile, low cost and longer-acting
piperaquine
makes it a very perfect candidate for use in combination with short and
rapidly acting
Active compound I. Piperaquinc of the present invention includes piperaquine
phosphate.
Piperaquine may be present in an amount of from about 40% to about 80%, w/w
based on
the total dosage form.
The total drug content of the oral dosage forms of the present invention is
within
the range of about 25% to about 85%, and in particular does not exceed 85% w/w
based
on the total dosage form.
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The oral dosage forms of the present invention comprise Active compound I and
piperaquine in a weight ratio of about 1:1 to about 1:10.
The oral dosage forms of the present invention comprise Active compound I
present in a dose range of about 100 mg to about 300 mg and piperaquine
present in a dose
range of about 700 mg to about 850 mg.
The oral dosage forms of the present invention comprise Active compound I
present in a unit dose of 100 mg, 150 mg or 250 mg and piperaquine present in
a unit dose
of 750 mg.
The oral dosage forms of the present invention comprise Active compound I in a
unit dose of about 100 mg and piperaquine present in a unit dose of about 750
mg.
The oral dosage forms of the present invention comprise Active compound I in a
unit dose of about 150 mg and piperaquine present in a unit dose of about 750
mg
The oral dosage forms of the present invention comprise Active compound Tin a
unit dose of about 200 mg and piperaquine present in a unit dose of about 750
mg
The dosage regimen of the present invention includes administering a fixed
dose
combination of 150 mg Active compound I and 750 mg of piperaquine once a day
for
three days.
The dose of Active compound I herein means dose equivalent to Active compound
I free base.
The dosage regimen of the present invention includes three doses over three
days.
The first dose is administered immediately on diagnosis, the second dose about
24 hours
after the first dose, and the third dose about 24 hours after the second dose.
The dosage regimen of the present invention is suitable for all patients aged
from
12 to 65 years and thus eliminates the need for calculating dose based on
individual weight
parameters. In the existing artemisinin based combinations, the dose is
calculated with
respect to the individual weight of the patient and in many cases the tablets
are scored to
adjust the dose. However, the dosage regimen of this combination is
surprisingly simple
and effective both for patients and for prescribers.
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Solid dosage form as used herein is selected from a group consisting of
tablets or
coated tablets, capsules, pellets, pills, granules and powders. A particularly
suitable solid
dosage form is that of tablets.
Further, it has been observed through exhaustive experimentation that when the
5 active compound is formulated into dosage forms, including liquid as well
as solid dosage
forms, it gets degraded by hydrolysis. The degradation may be due to water
associated
with the excipients or added during the course of processing. Thus, liquid
oral dosages
forms such as aqueous syrups, suspensions or solutions having desired shelf
life could not
be successfully prepared. Further, preparation of solid oral dosage forms of
active
10 compound using techniques involving use of water such as wet
granulation, spray drying,
or extrusion-spheronization processes resulted in dosage forms with wavering
stability
results. However, acceptable stability results were obtained when the solid
dosage forms
were formulated using appropriate excipients with low water content and a
process in
which water was absent, such as dry granulation, direct compression or non-
aqueous
15 granulation. In case where excipients were granulated using water, the
excipient granules
were dried appropriately before blending with the active compound as such or
with active
compound containing granules, and processed into solid dosage forms of
acceptable
stability.
The role of excipients and water content was evaluated by conducting
compatibility studies of the active compound with various excipients in
different
proportions, and evaluating the extent of degradation by forced degradation at
60 C over
the period of 2 weeks and at 50 C for 4 weeks. The water content was analyzed
using Karl
Fischer method and the total related substances (% w/w) were determined by
HPLC
method. The results of the study are represented below in Table 1.
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Table 1: Compatibility studies of active compound (Active compound I) with
various
excipients
Total Related Substance
(Percent w/w)
Water
Drug:After 4 After 2
Excipient (4)/ow/w) Initial
Excipient weeks/ weeks/
50 C 60 C
Croscarmellose sodium 1:0.5 0.59 0.09 0.34 0.35
Cross povidone 1:0.5 3.49 0.13 0.40 0.68
Sodium starch glycolate 1:0.5 1.43 0.13 0.43 0.89
Hydroxypropyl
1:0.5 1.22 0.17 0.70 1.05
methylcellulose 5cps
Polyvinyl pyrrolidone K 30 1:0.5 3.02 0.00 0.33 0.79
Sodium lauryl sodium 1:0.5 0.79 0.15 0.92 1.59
Opadryst 1:0.5 0.46 0.17 1.85 0.96
Titanium dioxide 1:0.5 0.18 0.16 0.57 0.93
Talc 1:0.1 0.12 0.15 0.63 0.90
Mg. Stearate 1:0.1 0.46 0.13 0.65 0.86
Aerosol 1:0.1 0.27 0.14 0.66 0.86
Polyethylene glycol 400 1:0.1 0.88 0.14 0.66 0.68
Microcrystalline cellulose 1:2 3.69 0.19 0.70 0.74
Starch 1:2 4.73 0.08 0.60 0.74
Dicalcium phosphate 1:2 2.01 0.07 0.77 1.32
Pearlitol 1:2 0.02 0.14 0.72 0.77
Micro crystalline cellulose 1:10 4.94 0.39 0.78 1.02
Starch 1:10 - 0.07 0.60 4.13
Dicalcium phosphate 1:10 2.14 0.17 0.61 6.07
Pearlitol 1:10 0.52 0.14 0.46 0.70
The study clearly indicates the importance of use of excipients having low
water or
moisture content in stabilizing solid dosage forms of the active compound. In
the present
invention, we have discovered that the use of excipients having water content
less than
6.5% w/w surprisingly increases the stability of the active compound, and thus
provides
reasonably long shelf lives. Starch was found to be incompatible with the
active
compound when used in higher amounts. Further, lactose was also found to be
incompatible due to degradation by other mechanisms such as Maillard reaction,
and
dicalcium phosphate was not preferred due to an increase in related substances
at 60 C.
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Microcrystalline cellulose, however, gave the most satisfactory results.
The stable solid oral dosage forms of the present invention may further
comprise
one or more pharmaceutically acceptable excipients, which include all
physiologically
inert excipients used in the art for the preparation of solid dosage forms.
Examples include
binders, diluents, glidants/lubricants, disintegrants, surfactants, coloring
agents, and the
like. The excipients may be used either intragranularly or extragranularly, or
both. The
weight ratio of active compound and excipients in the dosage forms may vary
from about
1.5:1 to about 1:30.
Examples of binders include methyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic,
ethyl cellulose,
polyvinyl alcohol, pullulan, agar, tragacanth and sodium alginate, or mixtures
thereof.
Examples of diluents include cellulose powdered, microcrystalline cellulose,
dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol,
mannitol, sorbitol,
sucrose, sugar compressible, and sugar confectioners, in particular
microcrystalline
cellulose. The diluents may be present in an amount from about 10% to about
40% w/w
based on the total weight of the dosage form. Further the weight ratio of
Active compound
Ito microcrystalline cellulose may vary from about 1:1 to about 1:5.
Examples of disintegrants include clays, celluloses, alginates, gums, cross-
linked
polymers (such as cross-linked polyvinylpyrrolidone and cross-linked sodium
carboxymethylcellulose), sodium starch glycolate, low-substituted
hydroxypropyl
cellulose and soy polysaccharides, in particular crospovidone. The
disintegrant may be
present in an amount from about 1% to about 10% w/w based on the total weight
of the
dosage form.
Examples of lubricants or glidants include talc, magnesium stearate, calcium
stearate, stearic acid, colloidal silicon dioxide, magnesium carbonate,
magnesium oxide,
calcium silicate, microcrystalline cellulose, mineral oil, waxes, glyceryl
behenate,
polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, sodium
laurylsulfate, sodium stearyl fumarate, and hydrogenated vegetable oils,
sucrose esters of
fatty acid, microcrystalline wax, yellow beeswax, white beeswax, in particular
magnesium
stearate. The lubricant may be present in an amount from about 1% to about 5%,
w/w
based on the total weight of the dosage form.
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Examples of surfactants include both non-ionic and ionic (cationic, anionic
and
zwifterionic) surfactants suitable for use in sweetener compositions. These
include
polyethoxylated fatty acids and its derivatives, for example polyethylene
glycol 400
distearate, polyethylene glycol--20 dioleate, polyethylene glycol 4-150 mono
dilaurate,
polyethylene glycol--20 glyceryl stearate; alcohol--oil transesterification
products, for
example polyethylene glycol--6 corn oil; polyglycerized fatty acids, for
example
polyglyceryl--6 pentaoleate; propylene glycol fatty acid esters, for example
propylene
glycol monocaprylate; mono and diglycerides, for example glyceryl ricinoleate;
sterol and
sterol derivatives; sorbitan fatty acid esters and its derivatives, for
example polyethylene
glycol--20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol
alkyl ether or
phenols, for example polyethylene glycol--20 cetyl ether, polyethylene glycol--
10-100
nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene-
-
polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for
example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl
fumarate,
propylene glycol alginate, octyl sulfosuccinate disodium, and palmitoyl
carnitine.
The coloring agents include any FDA approved colors for oral use.
The solid dosage forms may further be coated with one or more functional
and/or
non-functional layers comprising film-forming polymers, and other coating
additives.
Examples of film-forming polymers include cellulose derivatives such as ethyl
cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose,
methylcellulose,
carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
partially
hydrolyzed polyvinyl alcohol, cellulose acetate, hydroxypropyl methylcellulose
phthalate,
cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as
polyethylene
glycol; and methacrylic acid polymers such as Eudragit RL and RS.
Alternatively,
commercially available coating compositions comprising film-forming polymers
marketed
under various trade names, such as Opadryt, may also be used for coating.
The coating additives comprise one or more of plasticizers, glidants or flow
regulators, opacifiers and lubricants.
The pharmaceutical acceptable excipients and/or film forming polymers and
coating additives may be selected to provide an immediate-release profile or a
modified
release profile.
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Solid dosage forms of Active compound I may be prepared by densifying Active
compound I and one or more excipients, and processing into solid dosage forms.
Densification may be carried out using any conventional method known in the
art. In
particular, granulation or extrusion-spheronization may be used.
In one of the embodiments, stable oral tablets of Active compound I may be
prepared by a process comprising the steps of blending Active compound I and
intragranular portion of a diluent, lubricant, and disintegrant; passing the
blend through a
roller compactor to form a compact mass; reducing the compact mass into
granules of
suitable size; blending the granules with extragranular portion of a
lubricant, disintegrant,
and diluent in a double cone blender; and finally compressing into tablets
using suitable
tooling.
In another embodiment, stable oral tablets of Active compound I may be
prepared
by a process comprising the steps of blending Active compound I and
intragranular
portion of a diluent, lubricant, and disintegrant; compressing the blend in a
heavy
tabletting press to form slugs; reducing the slugs into granules of suitable
size; blending
the granules with extragranular portion of a lubricant, disintegrant, and
diluent in a double
cone blender; and finally compressing into tablets using suitable tooling.
In another embodiment, stable oral capsules of Active compound I may be
prepared by a process comprising the steps of blending Active compound I and
intragranular portion of a diluent, lubricant, and disintegrant; passing the
blend through a
roller compactor to form a compact mass; reducing the compact into granules of
a suitable
size; blending the granules with extragranular portion of a lubricant in a
double cone
blender; and finally filling into capsules of a suitable size.
In another embodiment, stable oral capsules of Active compound I may be
prepared by a process comprising the steps of blending Active compound I and
intragranular portion of a diluent, lubricant, and disintegrant; compressing
the blend in a
heavy tablet-ring press to form slugs; reducing the slugs into granules of a
suitable size;
blending the granules with extragranular portion of lubricant in a double cone
blender; and
finally filling into capsules of a suitable size.
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In another embodiment, stable oral tablets of Active compound I may be
prepared
by a process comprising the steps of blending Active compound I, a diluent, a
lubricant
and a disintegrant; and directly compressing into tablets using suitable
tooling.
In another embodiment, stable oral capsules of Active compound I may be
5 prepared by a process comprising the steps of blending Active compound I,
a diluent, and
a lubricant; and filling into capsules of a suitable size.
In another embodiment, stable oral tablets of Active compound I may be
prepared
by a process comprising the steps of blending Active compound I and
intragranular
portion of a diluent, and disintegrant; wet granulating the blend with a non
aqueous
10 granulating fluid or a solution/dispersion of pharmaceutically
acceptable excipients in the
non-aqueous granulating fluid; drying and reducing the granules to a suitable
size,
blending the granules with extragranular portion of a lubricant, disintegrant
and diluent in
a double cone blender; and finally compressing into tablets using suitable
tooling.
In yet another embodiment, stable oral capsules of Active compound I may be
15 prepared by a process comprising the steps of blending Active compound I
and
intragranular portion of diluent, and disintegrant; wet granulating the blend
with a non
aqueous granulating fluid or a solution/dispersion of pharmaceutically
acceptable
excipients in the non-aqueous granulating fluid; drying and reducing the
granules to a
suitable size; blending the granules with extragranular portion of lubricant
in a double
20 cone blender; and finally filling into capsules of a suitable size.
Examples of non-aqueous granulating fluid include organic solvents such as
methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, or mixtures
thereof
In yet another embodiment, tablets prepared by any of the above described
processes may further be coated with film-forming polymers and one or more
coating
additives, using techniques well known in the art such as spray coating in a
conventional
coating pan or a fluidized bed processor or dip coating. Alternatively,
coating can also be
performed using a hot melt technique.
The coating layers over the tablet may be applied as a solution/dispersion of
coating components in a suitable solvent. Examples of solvents used for
preparing a
solution/dispersion of the coating ingredients include methyl alcohol, ethyl
alcohol,
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isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform,
methylene chloride,
water and the like, and mixtures thereof.
In still another embodiment, one or more of another antimalarial drug selected
from piperaquine, lumefantrine, and DB 289 (pafuramidine maleate) may be added
in the
blend comprising active compound, in any of the embodiments above.
The dosage form of the present invention is processed and stored at a
temperature
below 27 C and relative humidity 50%.
The invention described herein is further illustrated by the following
examples,
which should not be construed as limiting the scope of the invention.
EXAMPLES
Example 1:
Ingredients Percent w/w
Intragranular
Maleate salt of a compound of Formula II (active 43.2
compound) [Active compound I]
Microcrystalline Cellulose 46.67
Magnesium stearate 0.75
Extragranular
Microcrystalline Cellulose 5.63
Croscarmellose sodium 3.0
Magnesium stearate 0.75
Total Percentage 100% _
Coating
Opadryt OY SS 58910 white 2.5
Water
Total weight 615
Water content <6.55% w/w
Procedure:
1. Active compound I and intragranular portion of microcrystalline
cellulose were
sieved through sieve BSS #44 and mixed together in a double cone blender to
form a
uniform blend.
2. To the blend of step 1, intragranular portion of sifted magnesium
stearate was
added and blended for about 5 minutes.
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3. The blend of step 2 was compacted in a roller compactor and was sifted
through
sieve BSS #22 to form granules.
4. Extragranular portion of microcrystalline cellulose, croscarmellose
sodium and
magnesium stearate were sieved through sieve BSS # 44 and blended with the
granules of
step 3.
5. The blend of step 4 was compressed using suitable size punches to obtain
compressed tablets.
6. The tablets as obtained from step 5 were coated with Opadry using
conventional
coating techniques.
The tablets prepared as per Example I were subjected to stability studies at
25 C/
RH 60%, 30 C/RH 65% and 40 C/RH 75% over a period of 6 months. The results are
summarized in Table 2. The results of in vitro drug release analyzed at
predetermined time
periods are given in Table 3.
Table 2: Total related substances* (Percent w/w)
Storage Condition Initial 1 month 2 months 3 months 6 months
25 C and 60% relative
0.11 0.27 0.28
humidity
30 C and 65% relative
0.11 0.37 0.27 0.29 0.34
humidity
40 C and 75% relative
0.11 0.55 0.67 1.40 1.82
humidity
* % Total Related Substance should not be more than 5% w/w.
Table 3: Percentage (%) of In vitro drug release in USP II apparatus* (media:
2%
tween 80 in water, 900m1 75 rpm, in 45 min)
Storage Condition Initial 1 month 2 months 3 months 6 months
C and 60% relative
93 101 95
humidity
C and 65% relative
93 98 93 94 96
humidity
Temperature 40 C and ,3 92
98 96 94
75% relative humidity
*The in vitro drug release (%w/w) should not be less than 70% (Q) of the
labeled amount
20 dissolved in 45 minutes.
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As evident from the above studies, the tablets prepared by the process of the
present invention in which water is absent shows acceptable shelf stability.
Example 2:
Ingredients Percent w/w
Maleate salt of a compound of Formula IT 44.33
(active compound) [Active compound I]
Microcrystalline Cellulose 51.17
Magnesium stearate 1.5
Croscarmellose sodium 3.0
Total weight 600 mg
Water content <6.5%
Procedure:
1. Active compound I, microcrystalline cellulose, croscarmellose sodium and
magnesium stearate were sifted through sieve BSS #44.
2. Sifted Active compound I, microcrystalline cellulose, and croscarmellose
sodium
were mixed in a double cone blender for about 15 minutes to form a uniform
blend.
3. To the blend of step 2, sifted magnesium stearate was added and mixed
for about 5
minutes.
4. The blend obtained in step 3 was directly compressed using suitable size
capsule
shape punches to obtain compressed tablets.
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Examples 3 and 4:
Ingredients Example 3 Example 4
Percent w/w Percent w/w
Intragranular
Maleate salt of a compound of Formula II (active 7.68 13.80
compound) [Active compound I]
Piperaquine phosphate 61.80 55.50
Microcrystalline Cellulose 20.39 21.15
Magnesium stearate 0.44 0.39
Crospovidone 2.21 1.99
Extragranular
Microcrystalline Cellulose 4.32 3.99
Crospovidone 2.11 1.99
Magnesium stearate 1.05 1.19
Total percentage 100% 100%
Coating
Opadrylt 02B53782 orange 2.5 2.5
Water q.s q.s
Total weight (mg) 1332.5 738
Water content <6.55% w/w <6.55% w/w
Procedure:
1. Active compound I, piperaquine phosphate and intragranular portion of
microcrystalline cellulose and crospovidone were sieved through sieve BSS # 44
and
mixed together in a double cone blender to form a uniform blend.
2. To the blend of step 1, intragranular portion of sifted magnesium
stearate was
added and blended for about 5 minutes.
3. The blend of step 2 was compacted in a roller compactor and was sifted
through
sieve BSS # 18 to form granules.
4. Extragranular portion of microcrystallinc cellulose and crospovidone
were sieved
through sieve BSS #44 and blended with the granules of step 3.
5. Extragranular portion of magnesium stearate was sieved through sieve BSS
# 44
and blended with the blend of step 4 in a double cone blender for about 5
minutes.
6. The blend of step 5 was compressed using suitable size punches to obtain
compressed tablets.
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7. The tablets as obtained from step 6 were coated with Opadry using
conventional
coating techniques and weight built of up to 2.5% w/w.
The tablets prepared as per the Example 3 & 4 were subjected to stability
studies at
40 C/RH 75% over a period of 3 months, as represented in Table 4.
5 Table 4: Percent total related substances* (Y0w/w)
1 2 3
Ingredient Initial
month months months
Maleate salt of a compound of Example 3 0.19 0.27 0.44
0.54
Formula II [Active compound I] Example 4 0.25 0.32 0.45 0.54
Example 3 1.16 1.1 1.11 1.16
Piperaquine phosphate
Example 4 1.15 1.03 1.13 1.16
* % Total related substance should not be more than 5% w/w.
Example 5:
Ingredients Percent w/w
Intragranular
Active compound I 14.60
Piperaquine phosphate 56.30
Microcrystalline Cellulose 16.70
Magnesium stearate 0.43
Crospovidone 2.15
Extragranular
Microcrystalline Cellulose 4.30
Crospovidone 2.15
Magnesium stearate 0.97
Coating
Opadry 02B53782 orange 2.40
Water q.s
Total weight (mg) 1332.0
Water content <6.55% w/w
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Procedure:
1. Active compound 1, piperaquine phosphate and intragranular portion of
microcrystalline cellulose and crospovidone were sieved through sieve BSS ti
44 and
mixed together.
2. To the blend of step 1, intragranular portion of sifted magnesium
stearate was
added and blended for about 5 minutes.
3. The blend of step 2 was compacted and compacts were sifted through sieve
BSS #
18 to form granules.
4. Extragranular portion of microcrystalline cellulose and crospovidone
were sieved
through sieve BSS #44 and blended with the granules of step 3.
5. Extragranular portion of magnesium stearate were sieved through sieve
BSS # 44
and blended with the blend of step 4 in a double cone blender for about 5
minutes.
6. The blend of step 5 was compressed using suitable size punches to obtain
compressed tablets.
7. The tablets as obtained from step 6 were coated with Opadry using
conventional
coating techniques and weight built of up to 2.4%w/w.
Table 5: Percentage (% w/w) of In vitro drug release of Active compound I,
from
example 5, in USP II apparatus* (media: 2% tween 80 in water, 900m1, 75 rpm)
Time (minutes) (Percent w/w)
15 88
30 87
45 90
*The in vitro drug release (% w/w) should not be less than 70% (Q) of the
labeled amount
dissolved in 45 minutes.
A Phase II, double blind, parallel group, randomized, dose finding study was
performed to determine the safety and efficacy of three dose levels (50 mg,
100 mg and
200 mg) of Active compound I administered for three days in patients with
uncomplicated
P. falciparum malaria. Preliminary data showed that the mean parasite
clearance time for
the patient on 50 mg was 52 hours, and all the 3 patients who were followed up
for 28
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days showed reappearance of parasites. Patients receiving 100 mg had a
parasite clearance
time of 46.6 hours and 5 of total 6 patients showed reappearance of parasites.
Patients
receiving 200 mg had a parasite clearance time of 30.4 hours and 4 out of 5
patients
showed adequate clinical and parasitological response (ACPR) at day 28. Only 1
patient
showed reappearance of parasites. The results obtained so far indicate that
Active
compound I was a short-acting drug and produced rapid clearance of parasites.
The
relatively high rate of recrudescence with Active compound I after three days
of
monotherapy highlighted the need to combine the drug with a long-acting drug.
Piperaquine phosphate was chosen as a partner drug and a Phase I double blind,
randomized, parallel group, placebo controlled study was conducted in young
healthy
male subjects to investigate the safety, tolerability and pharmacokinetic
profile of Active
compound I and piperaquine phosphate after co-administration of multiple oral
doses. The
study comprised of three cohorts. Cohort I received an oral daily dose of 100
mg of Active
compound I and 750 mg of piperaquine phosphate, Cohort II received an oral
daily dose of
200 mg of Active compound I and 750 mg of piperaquine phosphate and Cohort III
received an oral daily dose of 200 mg of Active compound I and 1000 mg of
piperaquine
phosphate. All three doses were administered once daily for three days in each
cohort. No
drug related adverse event was observed up to dose levels of 200 mg Active
compound I
and 750 mg of piperaquine phosphate. However, somnolence and vomiting were
reported
in dose level of 200 mg Active compound I and 1000 mg of piperaquine
phosphate.
Systemic exposures to Active compound I after repeated dosing was not
appreciably
different to that after single dose, hence no accumulation was observed for
Active
compound I upon 3 days repeated dosing of Active compound I - piperaquine
phosphate
combination. Exposures of Active compound I increased in a dose-proportional
manner
upon doubling the dose from 100 mg to 200 mg, when the dose of piperaquine
phosphate
was kept constant (Table 6).
0
ts.)
Table 6: Geometric mean pharmacoldnetic parameters of Active compound I (free
base) following multiple oral co-administration of
00
Active compound I and piperaquine phosphate to young healthy male subjects
(n=6). ot
Cohort Study T. (h) C. (ng/ml) T112 (h) AUC0_24 (ng.h/m1)
AUCo-i Ro
(ng.h/m1)
Day 1 Day 3 Day 1 Day 3 Day 1 Day 3 Day 1 Day 3
Day 1 Day 3
3.11 4.42 73.63 78.87 3.60 3.86 540.18
623.74 547.82 637.36 1.15
II 4.56 - 5.31 164.20 148.51 4.69 5.86 1388.18
1527.63 1458.61 1683.30 1.10 0
III 4.29 4.06 180.99 163.04 5.14 5.46 1573.19 1772.53 1670.89
1940.10 1.13
co
0
11.=Degree of accumulation calculated as (AUC0_24(Day 3)/AUC0_24 (Day 1))
0
co
00
0
0
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Comparative Bioavailability Study of fixed-dose combination of Active compound
I
150 mg + piperaquine phosphate 750 mg and co-pack formulations.
A single-dose, two-treatment, parallel design study comparing the
bioavailability
of fixed dose combination tablets of Active compound 1150 mg + piperaquine
phosphate
750 mg with co-administered Active compound 1150 mg and piperaquine phosphate
750
mg was conducted as an open label, balanced, randomized, single-dose, two-
treatment,
parallel design in 36 healthy, adult, human, male subjects under fasting
conditions. The
pharmacokinetic parameters are presented in Tables 7 and 8. The results of
this study
suggested that the pharmacokinetics of Active compound I remained unaltered
when
administered in fixed-dose combination with piperaquine phosphate as compared
to their
co-administration as individual tablets.
Table 7: Geometric mean pharmacokinetic parameters of Active compound I (free
base) following administration of fixed-dose combination (FDC) and co-pack
formulations of Active compound I and piperaquine phosphate to young healthy
male subjects.
T. (h) C. (ng/ml) AUC0_24 (ng.h/m1) AUCo-i T112 (h)
_ (ng.h/m1)
FDC Co- FDC Co- FDC Co- FDC Co- FDC Co-
pack pack pack pack pack
3.38 3.84 127.73 116.98 1143.01 1100.39 1146.70 1113.48 3.98 3.91
FDC: Fixed-dose combination tablet of Active compound 1150 mg and piperaquine
phosphate 750 mg as one tablet (n=16); Co-pack: Three Active compound I 50 mg
tablets
and one piperaquine phosphate 750 mg tablet as individual tablets (n=17),
AUCo_t= AUC
0 to last measurable concentration (sampling up to 96 h).
Table 8: Geometric mean pharmacokinetic parameters of piperaquine following
administration of fixed-dose combination (FDC) and co-pack formulations of
Active
compound I and piperaquine phosphate to young healthy male subjects.
T. (h) Cõ,õõ (ng/ml) AUC0_24 (ng.h/m1) AUCo-t
_(ng.h/m1)
FDC Co-pack FDC Co-pack FDC Co-pack FDC Co-pack
4.59 4.46 92.68 95.90 728.79 915.19 1431.48 1747.66
FDC: Fixed-dose combination tablet of Active compound 1150 mg and piperaquine
phosphate 750 mg as one tablet (n=16); Co-pack: Three Active compound I, 50 mg
tablets
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and one piperaquine phosphate 750 mg tablet as individual tablets (n=17),
AUCo_t= AUC
0 to last measurable concentration (sampling up to 96 h).
While several particular compositions have been described, it will be apparent
that
various modifications and combinations of the compositions detailed in the
text can be
5 made without departing from the spirit and scope of the invention.
