PHARMACEUTICAL COMPOSITION AND DOSAGE FORM
COMPRISING DRONEDARONE, AND PREPARATION METHOD
THEREOF
The present invention generally relates to a pharmaceutical
composition for oral administration containing an active principle with
antiarrhythmic activity. More precisely, the invention relates to a semi-solid
or liquid pharmaceutical composition intended to be used advantageously
in a dosage form of the capsule type, said composition comprising at least
one benzofuran derivative, as active principle, with antiarrhythmic activity
and at least one lipid excipient.
The present invention also relates to a method of preparing a
dosage form of this kind based on said pharmaceutical composition and
also relates to the therapeutic application of said composition or of said
dosage form.
"Benzofuran derivative with antiarrhythmic activity" denotes, in the
context of the present invention, a benzofuran compound selected from
those described in patents US 3248401, US 5223510 and EP 338746 as
well as in patent applications WO 88/07996, WO 89/02892, WO 90/02743
and WO 94/29289.
Among these compounds, we may mention, 2-n-buty!-3-[4-(3-di-n-
butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran or
dronedarone and the pharmaceutically acceptable salts thereof described
in patent EP1315709 as well as 2-n-butyl-3-(3,5-diiodo-4-
diethylaminoethoxybenzoyl)benzofuran or amiodarone and the
pharmaceutically acceptable salts thereof described in patent US 3248401.
Advantageously, the benzofuran derivative with antiarrhythmic
activity is selected from dronedarone or 2-n-butyl-3-[4-(3-di-n-
butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran of formula (D)
in the form of free base shown below and its derivatives, such as
pharmaceutically acceptable salts described hereunder.


"Pharmaceutically acceptable salt" means a salt which is not toxic to
the individual to whom it is administered when it is administered at standard
doses. Thus, as pharmaceutically acceptable salts of dronedarone we may
mention for example 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-
methylsulfonamidobenzofuran hydrochloride, 2-n-butyl-3-[4-(3-di-n-
butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran fumarate and
2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-
methylsulfonamidobenzofuran oxalate.
The antiarrhythmic compounds used in the context of the invention,
notably dronedarone and amiodarone, in the form of base, or salts thereof,
in particular the hydrochloride salts thereof, are characterized by low
solubility in aqueous media, which constitutes a major drawback for making
the active principle available by the oral route. Thus, these antiarrhythmic
compounds have low solubility in simulated gastric medium (3 mg/ml at pH
= 1.5) and very low solubility in simulated intestinal medium (1 ug/ml at pH
= 6.5).
As an example, the solubility curve of dronedarone hydrochloride at
room temperature and as a function of the pH shows maximum solubility of
about 1 to 2 mg/ml around pH of 3 to 5, but very low solubility at pH of the
order of 6 to 7, since it is no more than 10 ug/ml at pH = 7. As for
amiodarone hydrochloride, its solubility, at room temperature, is from 0.3 to
0.9 mg/ml in the pH range from 3 to 4 and a few ug/ml at pH = 7. Thus, it is
possible to dissolve 400 mg of dronedarone hydrochloride in 200 ml of
aqueous medium buffered at pH = 4 (0.1 M NaH2PO4 aqueous solution). In
contrast, in this medium diluted to 1/10 with an aqueous solution buffered
at pH = 7 (0.1 M Na2HPO4 aqueous solution), dronedarone hydrochloride is
precipitated (final pH of the medium = 6.7). As these solubility conditions

are similar to those recorded in the gastrointestinal tract, it can be assumed
that, in the stomach, dronedarone hydrochloride will be subject to acidic
conditions favorable to its dissolution, but once it enters the intestine, it will
in contrast encounter a medium with pH between 6 and 7, i.e. a
nonsolubilizing medium, in which it risks being precipitated.
Now, it is mainly in the intestine that absorption of the active
principle takes place, and it is now well known that administration by the
oral route requires optimal maintenance of the active principle in solution, in
the hope of obtaining sufficient permeation along the gastrointestinal tract,
and therefore acceptable exposure, for a significant therapeutic effect.
Taking into account the problem of solubility and bioavailability, a
dosage form has been developed and is currently on the market, in the
form of a film-coated tablet of 426 mg of dronedarone hydrochloride,
equivalent to 400 mg of dronedarone, sold under the trade name Multaq®,
for which the recommended dosage for adults is one tablet twice daily and
this must be taken with a meal for ensuring optimal action of said active
principle.
In fact, from the standpoint of pharmacokinetics, after oral
administration with a meal, dronedarone is absorbed well (at least 70%).
However, owing to presystemic first-pass metabolism, the absolute
bioavailability of this medicinal product (taken with food) is no more than
15%. The concomitant consumption of food multiplies the bioavailability of
the product by a factor of 2 to 4 relative to taking the medicine without
simultaneous ingestion of food. After oral administration with a meal, the
peak plasma concentrations of dronedarone and of its main circulating
active metabolite (N-debutylated metabolite) are reached in 3 to 6 hours.
The pharmacokinetics of dronedarone and of its N-debutylated metabolite
deviate moderately from the rule of proportionality to dose: doubling the
dose leads to an increase in Cmax and AUC by a factor of about 2.5 to 3.0.
Now, it is of course preferable for a patient to be able to have
therapeutic treatment without the constraint of taking medicine with or
without a meal, quite particularly in the area of the treatment of disorders of
cardiac rhythm, especially arrhythmias.
The development of a pharmaceutical composition for oral
administration of an active principle with antiarrhythmic activity, capable of
producing acceptable bioavailability, regardless of whether or not food is
ingested concomitantly, i.e. a composition involving a limited meal effect to
be effective, is therefore still of considerable interest.

A new pharmaceutical composition has now been found, quite
surprisingly and unexpectedly, allowing oral administration of at least one
antiarrhythmia active principle, advantageously 2-n-butyl-3-[4-(3-di-n-
butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran or a
derivative of the latter, for example a salt thereof, without the drawbacks
mentioned above. This composition, comprising at least one active
principle incorporated in a matrix consisting of the other ingredients of said
composition, in particular the other excipients, proves sufficiently stable and
has suitable solubility for surviving in the gastrointestinal tract until it
reaches the site of absorption. This composition can, moreover, be taken
on an empty stomach or with a snack or even a low-fat meal and in one or
more doses.
The present invention thus relates to a pharmaceutical composition
for oral administration of an active principle with antiarrhythmic activity,
such as for example 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-
methylsulfonamidobenzofuran (i) in the form of base, (ii) in the form of a
pharmaceutically acceptable salt, characterized in that it comprises,
besides said active principle, at least one amphiphilic lipid excipient with
HLB value between 2 and 20.
The present invention thus relates to a pharmaceutical composition
for oral administration of an active principle with antiarrhythmic activity,
such as for example 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-
methylsulfonamidobenzofuran (i) in the form of base, (ii) in the form of a
pharmaceutically acceptable salt, characterized in that it comprises,
besides said active principle, at least one amphiphilic lipid excipient with
HLB value between 1 and 20.
Said composition according to the invention can be in a dosage form
of the capsule type or semi-solid or liquid capsule. In fact, it can
advantageously be packaged in a dosage form of the capsule type, even
more advantageously of the hard capsule type.
The following terms are used in the context of the present invention:
> Capsule, a dosage form with a hard or soft shell;

> Hard capsule, a capsule with a hard shell, having two parts: a part called
the body and a part called the cap;
> Bioavailability, a term used for describing a pharmacokinetic property of
medicinal products, namely the fraction of a dose that reaches the
bloodstream. It evaluates the amount of medicinal product absorbed that
reaches the bloodstream and the rate of absorption of said medicinal
product;

> Active principle, any substance possessing a therapeutic effect, for
example an antiarrhythmic effect. In the context of the invention, it is in
particular any benzofuran derivative with antiarrhythmic activity, defined
below, in particular dronedarone in the form of base, in the form of
pharmaceutically acceptable salts of addition to organic or inorganic acids.
Said salts can be prepared with pharmaceutically acceptable acids, but the
salts of other acids that can be used, for example, for purification or
isolation of the compounds of formula (I) also form part of the invention.
> Excipient, any substance that is inactive or inert with respect to a living
organism, in contrast to the active principle, and which facilitates the
preparation and administration of a medicinal product;
> Lipid excipient, any excipient known by a person skilled in the art as a
lipid solvent, advantageously amphiphilic, having an HLB value (term
defined below), which according to the invention is below 20 and above 1;
> Matrix, all the ingredients other than the active principle or principles of
the composition according to the invention, in particular the excipients;
> HLB value, the value of the hydrophilic-lipophilic balance, according to
the classification developed by Griffin, which is well known by a person
skilled in the art;

> Surfactant, an excipient, which through its amphiphilic properties
facilitates the wetting of powders, improves solubility/dissolution and/or
slows reprecipitation;
> Co-solvent, any solvent improving the feasibility of the method of
manufacture of the composition according to the invention on the basis of
the key parameters of viscosity and melting point of the matrix of said
composition as well as dissolution or dispersion of the active principle in
said matrix;
> Diluent, an excipient used for obtaining a sufficient volume of
composition for manufacturing a dosage form, for example a hard capsule,
of the desired size and possessing suitable physical characteristics for the
method of manufacture selected for the hard capsule;

> Disintegrant, an excipient that provides satisfactory disintegration of the
dosage form and therefore disintegration of the active principle in the
stomach by increasing the friability and by reducing the hardness of the
dosage form;
> Antiadherent, an excipient intended to prevent the particles sticking to
one another and to the manufacturing equipment during manufacture of the
dosage form, for example when filling the capsules.
> Lubricant, an excipient intended to facilitate the steps in manufacture of
the dosage form, owing to their role in sliding, i.e. consisting of increasing
the flowability of the particles in the pipework of the machines;
> Plasticizer, an excipient intended to permit constant release of the active
principle from the dosage form by being interposed between the polymer
chains and by allowing them to slide relative to one other. It is selected in
relation to its solubility.
Among the compositions according to the invention, we may
mention a first group of pharmaceutical compositions comprising:
• 1-60 wt% of at least one active principle according to the invention,
advantageously between 1 and 50%, even more advantageously
between 10 and 45%, even better between 20% and 40%;
• 40-99 wt% of at least one lipid excipient according to the invention,
advantageously between 45 and 80%, even more advantageously
between 50% and 60%,
• 0-30 wt% of at least one compound selected from surfactants, co-
solvents, diluents, disintegrants, lubricants, organic or inorganic
bases and plasticizers, advantageously from 1 to 20%, even better
from 1 to 10%,
the percentages being expressed by weight relative to the total weight of
said composition.
Among the compositions according to the invention, we may
mention a second group of pharmaceutical compositions comprising:
• 1-60 wt% of at least one active principle according to the invention,
advantageously between 1 and 50%, even more advantageously
between 10 and 45%, even better between 20% and 40%;
• 37-99 wt% of at least one lipid excipient according to the invention,
advantageously between 45 and 80%, even more advantageously
between 45% and 55%,

• 0-30 wt% of at least one compound selected from surfactants, co-
solvents, diluents, disintegrants, lubricants, organic or inorganic
bases and plasticizers, advantageously from 1 to 20%, even better
from 1 to 10%,
the percentages being expressed by weight relative to the total weight of
said composition.
Among the compositions according to the invention, we may
mention a third group of pharmaceutical compositions comprising:
• 1-60 wt% of at least one active principle according to the invention,
advantageously between 1 and 50%, even more advantageously
between 10 and 45%, even better between 20% and 40%;
• 40-99 wt% of at least one lipid excipient according to the invention,
advantageously between 45 and 80%, even more advantageously
between 50% and 60%,
• 0-30 wt% of at least one surfactant, advantageously between 1 %
and 20%, even more advantageously between 5% and 15%, and
• 0-29 wt% of at least one co-solvent, advantageously between 1 and
20%, even more advantageously between 2 and 15%;
the percentages being expressed by weight relative to the total weight of
said composition. The total of the compositions comes to 100 wt%.
Among the compositions according to the invention, we may
mention a fourth group of pharmaceutical compositions comprising:
• 1-60 wt% of at least one active principle according to the invention,
advantageously between 1 and 50%, even more advantageously
between 10 and 45%, even better between 20% and 40%;
• 37-99 wt% of at least one lipid excipient according to the invention,
advantageously between 45 and 80%, even more advantageously
between 50% and 60%,
• 0-30 wt% of at least one surfactant, advantageously between 1 %
and 20%, even more advantageously between 5% and 10%, and
• 0-29 wt% of at least one co-solvent, advantageously between 1 and
20%, even more advantageously between 2 and 15%;
the percentages being expressed by weight relative to the total weight of
said composition. The total of the compositions comes to 100 wt%.

Among the compositions according to the invention, we may
mention a fifth group of pharmaceutical compositions comprising:
• 60-200 wt% of at least one lipid excipient according to the invention,
advantageously between 120 and 180%, even more advantageously
180%
• 0-30 wt% of at least one surfactant, advantageously between 5%
and 30%, even more advantageously between 10% and 30%,
• 0-30 wt% of at least one co-solvent, advantageously between 1 and
20%;
the percentages being expressed by weight relative to the total weight of
the active principle.
The pharmaceutical compositions according to the invention
comprise at least one active principle with antiarrhythmic activity and at
least one lipid excipient.
Among the active principles with antiarrhythmic activity according to
the invention, we may mention 2-n-butyl-3-[4-(3-di-n-
butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran in the form of
base or dronedarone and the pharmaceutically acceptable salts thereof
described in patent EP1315709.
As pharmaceutically acceptable salts, we may mention for example
2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-
methylsulfonamidobenzofuran hydrochloride, 2-n-butyl-3-[4-(3-di-n-
butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran fumarate and
2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-
methylsulfonamidobenzofuran oxalate.
Advantageously, the composition according to the invention
comprises 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-
methylsulfonamidobenzofuran or 2-n-butyl-3-[4-(3-di-n-
butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran hydrochloride
as active principle.
According to one variant, dissolution of the active principle in its
base form can be obtained starting from pharmaceutically acceptable salts
of dronedarone, as mentioned above, and by reforming the active principle
in its base form in situ by change of pH with an organic or inorganic base.
The compositions according to the invention comprising at least one
pharmaceutically acceptable salt of dronedarone, and further comprising at

least one organic or inorganic base, advantageously in stoichiometric molar
amount relative to the active principle in the form of base, form part of the
present invention.
As a guide, the nature of the base that can be used in the
composition can be organic, for example ethanolamine, or mineral such as
for example soda or potash. Advantageously, it is soda.
The active principle or principles according to the invention is or are
present in the composition according to the invention in a proportion in the
range 1-60 wt%, advantageously between 1 and 50%, even more
advantageously between 10 and 45%, even better between 20% and
40 wt% relative to the total weight of the composition.
The lipid excipient is an amphiphilic lipid excipient with HLB value
between 1 and 20 and whose melting point is below 50°C.
The lipid excipient is an amphiphilic lipid excipient with HLB value
between 2 and 20 and whose melting point is below 50°C.
A distinction is made between amphiphilic excipients that are semi-
solid at room temperature and amphiphilic excipients that are liquid at room
temperature.
The lipid excipient according to the invention can be selected from:
• semi-solid substituted glycerides,
• liquid substituted glycerides,
• semi-solid substituted polyoxylglycerides,
• liquid substituted polyoxylglycerides,
• and mixtures thereof.
We may mention, for example, a group in which the lipid excipient is
selected from:
• as semi-solid substituted glycerides according to the invention, the
Gelucires marketed for example under the brand name Gelucire®
33/01, Gelucire® 39/01, Gelucire® 43/01 and Geleol®, Peceol™,
• as liquid substituted glycerides according to the invention, those
marketed for example under the name Labrafac Lipophile® WL1349,

• as semi-solid substituted polyoxylglycerides according to the
invention, the Gelucire marketed for example under the brand name
Gelucire®44/14, Gelucire®50/13,
• as liquid substituted polyoxylglycerides according to the invention,
those marketed for example under the brand name
Labrafil®M1944CS, Labrafil®M2125CS, Labrafil®M2130CS and
Labrasol®.
We may mention, for example, another group in which the lipid
excipient is selected from semi-solid substituted polyoxylglycerides
according to the invention, the commercially available Gelucire, more
particularly the lauroyl macroglyceride marketed under the brand name
Gelucire®44/14.
When the active principle is in the form of a salt, the composition can
be in the form of a dispersion of said solid active principle in a solid matrix
at room temperature in the case when a semi-solid lipid excipient is used in
a sufficient amount or in the form of a dispersion of a solid in an oil at room
temperature in the case when a liquid lipid excipient is used in a sufficient
amount, the solubility of said active principle in the composition being
moreover a function of the pH of the medium in which the composition is
contained.
The amphiphilic lipid excipient, semi-solid at room temperature, of
the composition according to the invention, has the advantage of permitting
a solid dispersion or hot dissolution of the active principle in the matrix of
said composition and of facilitating dissolving of the active principle on
dissolution of the matrix in the gastric and/or intestinal aqueous
environment.
The amphiphilic lipid excipient, liquid at room temperature, of the
composition according to the invention, has the advantage of facilitating
dissolving of the active principle in the gastric and/or intestinal aqueous
environment.
Advantageously, the composition according to the invention
comprises at least one amphiphilic lipid excipient, having an HLB value
between 5 and 18.

The amphiphilic lipid excipients, with HLB value between 5 and 18,
according to the invention, can be selected from the group comprising:
• the medium-chain mono- and diglycerides, for example Capmul
MCM® (HLB value between 5.5 and 6), marketed by the company
Abitec,
• propylene glycol monolaurate, for example Lauroglycol® 90 (HLB
value equal to 5) and Capmul PG12®, marketed by the companies
Gattefosse and Abitec respectively,
• the caprylocaproyl macrogol-8 glycerides, for example Labrasol®
(HLB value equal to 14), marketed by the company Gattefosse,
• the lauroyl macrogolglycerides, for example Gelucire® 44/14 (HLB
value equal to 14) and Gelucire® 50/13 (HLB value equal to 13),
marketed by the company Gattefosse,
• propylene glycol caprylic acid monoester, for example Capmul® PG-
8 (HLB value equal to 6), marketed by the company Abitec,
• and mixtures thereof.
More particularly, the amphiphilic lipid excipient with HLB value between 5
and 18 is selected from the group comprising Capmul MCM®, Lauroglycol®
90, Capmul PG12®, Labrasol®, Gelucire® 44/14, Gelucire® 50/13, Capmul®
PG-8, and mixtures thereof.
According to one embodiment, the lipid excipients according to the
invention are selected from the amphiphilic lipid excipients, having an HLB
value between 12 and 18.
The lipid excipient or excipients according to the invention is or are
present in the composition according to the invention in a proportion in the
range 40-99 wt%, advantageously between 45 and 80%, even more
advantageously between 50% and 60 wt% relative to the total weight of the
composition.
The lipid excipient or excipients according to the invention is or are
present in the composition according to the invention in a proportion in the
range 37-99 wt%, advantageously between 45 and 80%, even more
advantageously between 50% and 60 wt% relative to the total weight of the
composition.

The lipid excipient or excipients according to the invention is or are present
in the composition according to the invention in a proportion in the range
100-200 wt%, advantageously between 110 and 180%, even more
advantageously between 50% and 60 wt% relative to the total weight of the
active principle.
The pharmaceutical compositions according to the invention can
further comprise at least one surfactant and/or at least one co-solvent.
The surfactant is advantageously hydrophilic and/or nonionic. It can
be selected from:
• ethylene oxide/propylene oxide copolymers, called poloxamers
hereinafter, such as poloxamer 124 marketed under the brand name
SYNPERONIC PE/L44; poloxamer 188 marketed under the brand name
PLURONIC F68 or SYNPERONIC PE/F68; poloxamer 237 marketed under
the brand name PLURONIC F87 or SYNPERONIC PE/F87; poloxamer 338
marketed under the brand name SYNPERONIC PE/F108 or poloxamer 407
marketed under the brand name PLURONIC F127, SYNPERONIC
PE/F127orLUTROLF127;
• polyethoxylated castor oils, such as those marketed under the
brand name CREMOPHOR RH40;
• ethoxylated polysorbates, such as polysorbate 20, polysorbate 40,
polysorbate 60 and polysorbate 80 marketed respectively under the brand
names TWEEN 20, TWEEN 40, TWEEN 60, and TWEEN 80; and
• polyethylene hydroxystearates, such as polyethylene
hydroxystearate 660 marketed under the brand name SOLUTOL HS15.
More particularly, the surfactant can be selected from:
• ethylene oxide/propylene oxide copolymers, called poloxamers
hereinafter, such as poloxamer 124 marketed under the brand name
SYNPERONIC PE/L44; poloxamer 188 marketed under the brand name
PLURONIC F68 or SYNPERONIC PE/F68; or poloxamer 407 marketed
under the brand name PLURONIC F127, SYNPERONIC PE/F127 or
LUTROLF127;
• polyethoxylated castor oils, such as those marketed under the
brand name CREMOPHOR RH40;
• ethoxylated polysorbates, such as polysorbate 60 marketed under
the brand name TWEEN 60; and

said composition, advantageously the co-solvent is propylene glycol and/or
at a content of about 20 wt%.
According to one embodiment, the co-solvent is a glycol derivative,
substituted and/or at a content below 30 wt% relative to the total weight of
active principle, advantageously the co-solvent is propylene glycol and/or at
a content of about 20 wt% relative to the total weight of the active principle.
According to one embodiment, the composition according to the invention
comprises:
• 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-
methylsulfonamidobenzofuran or 2-n-butyl-3-[4-(3-di-n-
butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran
hydrochloride in the form of base, as active principle,
and/or
• at least one semi-solid lipid excipient with HLB between 1 and 20,
advantageously between 5 and 18, even more advantageously
between 12 and 18, advantageously selected from the semi-solid
substituted glycerides and the semi-solid substituted
polyoxylglycerides, advantageously it is Gelucire®44/14,
and/or
• at least one surfactant, advantageously selected from the ethylene
oxide/propylene oxide copolymers called poloxamers, even more
advantageously it is poloxamer 407,
and optionally at least one co-solvent as defined above.
This pharmaceutical composition is in a liquid or semi-solid form, i.e.
of a pasty consistency, depending on the consistency and nature of the
excipient or excipients used, among others of the lipid excipient, at room
temperature. A lipid or semi-solid excipient at room temperature will give
rise to the formation of a semi-solid matrix and therefore to a composition
according to the invention of a pasty consistency whereas a lipid excipient
that is liquid at room temperature will give rise to the formation of a liquid
matrix and therefore to a composition according to the invention of a liquid
consistency.
Thus, in the case when the lipid excipient according to the invention
is selected from the lipid or semi-solid excipients, the composition
according to the invention can be prepared by employing known methods

for solubilization or cold or hot solid dispersion in the lipid excipient forming
a lipid matrix. The manufacture of the composition consists, for example, of
dissolving or dispersing the active principle according to the invention and
optionally other excipients according to the invention, in said lipid excipient
at a temperature from about 30°C to 60°C, for example a temperature of
about 44°C, said temperature being selected as a function of the melting
point of said lipid excipient used.
According to a particularly advantageous embodiment, the method
of manufacturing the composition according to the invention consists of
dissolving the active principle, advantageously 2-n-butyl-3-[4-(3-di-n-
butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran in the form of
base, at about 44°C in the lipid excipient, advantageously lauryl
macroglycerides, for example Gelucire® 44/14.
In the case when the lipid excipient, according to the invention, is
selected from the liquid lipid excipients, the composition according to the
invention can be prepared by employing known methods of dissolving or
dispersing the active principle in the lipid excipient, forming a lipid matrix
that is liquid at room temperature.
The methods of preparing the pharmaceutical compositions
according to the invention are carried out by the conventional techniques
known by a person skilled in the art.
The liquid or semi-solid pharmaceutical composition according to the
invention, thus obtained, can then be incorporated in a hard capsule, as it
is. Encapsulation is carried out according to the conventional methods of
encapsulation, taking into account the physicochemical constraints of said
composition and of said method.
Said composition can optionally be transformed into powders, which
can be granulated or optionally can be incorporated in capsules or used as
they are.
The invention thus also relates to a dosage form comprising a
• pharmaceutical composition according to the invention.
This dosage form can be in the form of a capsule containing the
composition according to the invention or optionally in the form of powders
or granules that can be supplied in multidose containers or in the form of
unit doses such as packets or sachets.

Capsules are solid preparations consisting of a hard or soft shell, of
variable shape and capacity, generally containing a unit dose of active
principle. The shell is based on gelatin or other natural or synthetic
substances whose consistency can be adjusted by adding for example
glycerol or sorbitol. Other excipients such as surfactants, opacifiers,
antimicrobial preservatives, sweeteners, colorants and/or flavorings can
also be added to the composition of the capsule shells.
We may mention as capsules: hard capsules, soft shell capsules,
enteric capsules and modified-release capsules.
Advantageously, the dosage form according to the invention is a
hard capsule.
The method of manufacture of hard capsules comprising a body and
a cap consists of (i) preparing the composition according to the invention by
mixing the ingredients as defined above and then (ii) filling the cap and/or
body parts of the capsule by volumetric distribution by a method that is
suitable for powders (compressing/metering apparatus, a leveling method,
a method with alternating leveling and packing or tamping, an endless-
screw method or a method of cell metering) or for semi-solids (casting of
the molten or liquid product), and finally closing the capsules by joining
together the parts forming the cap and body of said capsule.
In the case of soft capsules the liquid preparation is poured at the
same time as the capsule is formed in the dies according to the
conventional method of manufacture.
As a nonlimiting guide, the amount of active principle can vary from 50 to
500 mg per dosage unit such as for example (i) a capsule, advantageously
a hard capsule, or (ii) a sachet of powders, or granules, and the amount of
lipid excipient between 0.5 and 100 mg. Preferably, a dosage form
according to the invention, for example a hard capsule, can comprise from
200 to 400 mg of active principle.
The pharmaceutical composition according to the invention and the dosage
form comprising said composition aim to limit the meal effect after oral
administration in humans. The lipid excipient makes it possible on the one
hand to solubilize the active principle according to the invention and on the
other hand to protect it from the negative effects of the pH in the intestinal
tract, thus permitting significant avoidance of the meal effect. The presence

of a surfactant, for example poloxamer, in said composition makes it
possible to limit the reprecipitation and agglomeration of the active principle
while in the gastrointestinal tract.
Fig. 1 shows the dissolution curves of hard capsules according to the
invention (Hard Capsules G1 to Hard Capsules G6), of a comparative
reference hard capsule and of a comparative tablet with 10% of poloxamer,
all these formulations containing active principle according to the invention.
Fig. 2 shows the dissolution curves of hard capsules according to the
invention (Capsules G4 to Capsules G8), all these formulations containing
active principle according to the invention.
Fig. 3 shows the dissolution curves of hard capsules according to the
invention (Capsules G1, G3, G9), all these formulations containing active
principle according to the invention.
Fig. 4 shows the dissolution curves of hard capsules according to the
invention (Capsules G5, G10, G13), all these formulations containing active
principle according to the invention.
Fig. 5 shows the dissolution curves of hard capsules according to the
invention (Capsules G1, G9, G11, G12), all these formulations containing
active principle according to the invention.
Fig. 6 shows the dissolution curves of hard capsules according to the
invention (Capsules G1, G22, G24, G26, G28), all these formulations
containing active principle according to the invention.
Fig. 7 shows the dissolution curves of hard capsules according to the
invention (Capsules G5, G23, G25, G27, G29), all these formulations
containing active principle according to the invention.
These curves express the percentage by weight of active principle released
as a function of time, expressed in minutes. The vertical line shown in bold
at 60 min marks the moment when an alkaline solution of NaOH is added
to the simulated gastric medium in order to simulate an intestinal medium.

EXAMPLES
Table A below shows the solubility of dronedarone hydrochloride and of
dronedarone base form in lipid excipients according to the invention.


Compositions according to the invention were manufactured, with the
composition shown in detail in Tables 1, 3 and 4 below.
Comparative compositions, not according to the invention, were
manufactured with the composition detailed in Table 2 below. The amounts
of compounds used for making said compositions are expressed in mg in
said Tables 1 and 2.
"-" signifies absence of the composition.
"QS" signifies in sufficient quantity.
"HCI Salt" signifies dronedarone hydrochloride.
"Base" signifies dronedarone base form.
"Pol." signifies "poloxamer".
"Geluc." signifies "Gelucire".
"Crem. RH40" signifies "Cremophor RH40)"

Opaque white capsules of size 0 were then manufactured using the
compositions from the examples given below and using comparative
composition 2 for obtaining hard capsules G1-G29 according to the
invention and a hard capsule not according to the invention, i.e. reference
hard capsule. Comparative composition 1, not according to the invention,
was used for making a tablet that is not according to the invention.

The equipment required for making the compositions and the hard
capsules, for which the procedures are described below, is as follows:
Magnetic stirrer, Beaker, Precision balance adjusted to the amount
weighed, Sieve 0.315 mm, Water bath, Gilson Pipette 1000 uL piston-type,
Capsuling machine.

Moreover, the Gelucire 44/14 used for making the compositions is
stoved at 55°C in the evening of the day before manufacture.
Homogenization is done manually by inverting the pot.
Manufacture of hard capsule G1:
Procedure:
- Weigh the Geiucire® 44/14 previously melted in the beaker used for
manufacture,
- Sieve the dronedarone in the form of hydrochloride at 0.315 mm mesh
before weighing,
- Melt and mix the Gelucire® 44/14 and poloxamer 407, stirring slowly at a
stirrer speed of 200 rpm for about 10 min at a water bath temperature of
55-60°C,
- Add the propylene glycol at a stirrer speed of 200 rpm and at a water bath
temperature of 55-60°C,

- Slowly add, and disperse with vigorous stirring, the previously sieved
dronedarone hydrochloride at a speed during addition of 300-650 rpm.
After addition, mix for 30 min at a mixing speed of 500 rpm and at a water
bath temperature of 55-60°C,
- With an automatic pipette, fill opaque white hard capsules size 0. Fill the
capsules with unit weights. The stirring speed during distribution is 500 rpm
and the water bath temperature is 55-60°C,
- After closure, arrange the capsules in the vertical position on the
capsuling machine for solidification at room temperature.
Manufacture of hard capsule G2:
Procedure:
- Weigh the Gelucire® 44/14 previously melted in the beaker used for
manufacture,
- Sieve the dronedarone in the form of hydrochloride at 0.315 mm mesh
before weighing,
- Melt and mix the Gelucire® 44/14 and poloxamer 407, stirring slowly at a
stirrer speed of 200 rpm for about 10 min at a water bath temperature of
55-60°C,
- Slowly add, and disperse with vigorous stirring, the previously sieved
dronedarone hydrochloride at a speed during addition of 300-650 rpm.
After addition, mix for 10 min at a mixing speed of 500 rpm at a water bath
temperature of 55-60°C,

- Add 27% sodium hydroxide solution at a stirring speed of 500 rpm. After
addition, mix for 30 min at a water bath temperature of 55-60°C,
- With an automatic pipette, fill opaque white hard capsules size 0. Fill the
capsules with unit weights. The stirring speed during distribution is 500 rpm
and the water bath temperature is 55-60°C,
- After closure, arrange the capsules in the vertical position on the
capsuling machine for solidification at room temperature.
Manufacture of hard capsule G3:
Procedure:
- Weigh the Gelucire® 44/14 previously melted in the beaker used for
manufacture,
- Sieve the dronedarone in the form of hydrochloride at 0.315 mm mesh
before weighing,
- Slowly add, and disperse with vigorous stirring, the previously sieved
dronedarone hydrochloride at a speed during addition of 300-650 rpm.
After addition, mix for 30 min at a mixing speed of 350 rpm and at a water
bath temperature of 55-60°C,
- With an automatic pipette, fill opaque white hard capsules size 0. Fill the
capsules with unit weights. The stirring speed during distribution is 500 rpm
and the water bath temperature is 55-60°C,
- After closure, arrange the capsules in the vertical position on the
capsuling machine for solidification at room temperature.
Manufacture of hard capsule G4:
Procedure:
- Weigh the Gelucire® 44/14 previously melted in the beaker used for
manufacture,
- Sieve the dronedarone at 0.315 mm mesh before weighing,
- Melt and mix the Gelucire® 44/14 and poloxamer 407, stirring slowly at a
stirrer speed of 200 rpm for about 10 min at a water bath temperature of
55-60°C,
- Gradually add and dissolve the previously sieved dronedarone in its base
form, stirring vigorously at a speed during addition of 300-650 rpm. After
addition, mix for 30 min at a mixing speed of 500 rpm and at a water bath
temperature of 55-60°C,
- Gradually add the water, stirring at a stirrer speed of 500 rpm for about 10
min and at a water bath temperature of 55-60°C,

- With an automatic pipette, fiil opaque white hard capsules size 0. Fill the
capsules with unit weights. The stirring speed during distribution is 500 rpm
and the water bath temperature is 55-60°C,
- After closure, arrange the capsules in the vertical position on the
capsuling machine for solidification at room temperature.
Manufacture of hard capsule G5:
Procedure:
- Weigh the Gelucire® 44/14 previously melted in the beaker used for
manufacture,
- Sieve the dronedarone at 0.315 mm mesh before weighing,
- Melt and mix the Gelucire® 44/14 and poloxamer 407, stirring slowly at a
stirrer speed of 200 rpm for about 10 min at a water bath temperature of
55-60°C,
- Add the propylene glycol at a stirrer speed of 200 rpm and at a water bath
temperature of 55-60°C,
- Gradually add and dissolve the previously sieved dronedarone in its base
form, stirring vigorously at a speed during addition of 300-650 rpm. After
addition, mix for 30 min at a mixing speed of 500 rpm and at a water bath
temperature of 55-60°C,
- With an automatic pipette, fill opaque white hard capsules size 0. Fill the
capsules with unit weights. The stirring speed during distribution is 500 rpm
and the water bath temperature is 55-60°C,
- After closure, arrange the capsules in the vertical position on the
capsuling machine for solidification at room temperature.
Manufacture of hard capsule G6:
Procedure:
- Weigh the Gelucire® 44/14 previously melted in the beaker used for
manufacture,
- Sieve the dronedarone at 0.315 mm mesh before weighing,
- Melt and mix the Gelucire® 44/14, stirring slowly at a stirrer speed of 200
rpm for about 10 min at a water bath temperature of 55-60°C,
- Gradually add and dissolve the previously sieved dronedarone in its base
form, stirring vigorously at a speed during addition of 300-650 rpm. After
addition, mix for 30 min at a mixing speed of 500 rpm and at a water bath
temperature of 55-60°C,

- With an automatic pipette, fill opaque white hard capsules size 0. Fill the
capsules with unit weights. The stirring speed during distribution is 500 rpm
and the water bath temperature is 55-60°C,
After closure, arrange the capsules in the vertical position on the capsuling
machine for solidification at room temperature.
The reference hard capsule is produced according to the same protocol as
for capsule G6 with the proportions and the ingredients as indicated in
Tables 1 and 2 above. The tablet consisting of comparative composition 1
as indicated in Table 2 is manufactured according to the usual techniques
for manufacture of dosage forms of this kind.
Hard capsules G7 to G29 are produced according to the same protocol as
for capsule G6 with the proportions and the ingredients as indicated in
Tables 3 and 4 above.
EVALUATION OF DISSOLUTION OF THE ACTIVE PRINCIPLE OF THE
PHARMACEUTICAL COMPOSITION IN AQUEOUS MEDIUM WHILE PASSING THROUGH
THE GASTROINTESTINAL TRACT
In order to reproduce the effect of pH on the active principle and in
particular on its dissolution during its passage through the gastrointestinal
tract, a gastrointestinal environment was simulated by reproducing the pH
of the stomach and then the pH of the intestine with a jump in pH. The
dissolution kinetics was investigated using a simple in-vitro dissolution test
with a jump in pH.
OOOPrinciole:
The principle consists of determining the dissolution of the
formulated active principle by studying its dissolution kinetics at 37°C, firstly
in simulated gastric medium at pH 4, then in simulated intestinal medium at
pH 6.5, in a time interval consistent with the gastrointestinal tract.
• OOOEquipment and method
OOOEquipment: precision balance (Mettler AE200 or AT261), pH meter
(Knick or Schott Gerate or Inolab), thermostated Dissolutest 6 or 7 bowls
(Sotax AT6 or AT7), 5 urn filter (PALL Versapore 25 mm) with syringe

(Terumo), UV spectrophotometer (Gilford Response II or Perkin Elmer) or
HPLC (Merck or Agilent).
Dissolution media: The simulated physiological media representative of the
gastrointestinal tract are obtained from simulated gastric and intestinal
fluids recommended by the USP, but used without pepsin or pancreatin.
* simulated gastric fluid - USP (without pepsin):
- 2 g of sodium chloride per 900 ml of distilled water,
- pH adjusted to 1.2 with concentrated hydrochloric acid (37%),
- Q.S. 1000 ml with distilled water.
• simulated intestinal fluid - USP (without pancreatin):
- 6.8 g of potassium dihydrogen phosphate per 900 ml of distilled
water,
- pH adjusted to 7.5 with concentrated sodium hydroxide (10 M),
- Q.S. 1000 ml with distilled water.
The simulated gastric medium of pH 4 is thus obtained by mixing the two
simulated fluids in various proportions, monitoring with a pH electrode.
The dissolution medium of the intestinal type is adjusted to pH 6.5 with a
few drops of concentrated soda (10M) to simulate passage of the active
principle into the beginning of the intestine, without leading to dilution.
Method:
• Calibration: Standard solutions of active principle are prepared in a
solvent medium, preferably in the mobile phase or ethanol or methanol,
and then analyzed at the characteristic wavelength of the active principle. A
calibration straight line showing the concentrations as a function of the
optical densities (analysis by UV spectrophotometry) or of the areas under
peak (HPLC analysis) is then determined. The equation of the straight line
obtained can be used for determining the concentration of dissolved active
principle from measurement of the optical density or of the area under
peak.
• OOODissolution kinetics: The concentration used corresponds to
the dose in 250 ml (i.e. 4 capsules in a 500-ml bowl). The dissolution
kinetics is first investigated in simulated gastric medium of pH 4 in the
dissolution test in bowls thermostated at 37°C, with paddle stirring at 75
rpm, for 1 hour with sampling at times 5, 15, 30, 45 and 60 minutes, then in
intestinal medium with an increase in pH to 6.5 by adding a small volume of
concentrated soda (example: 0.400 ml for 500 ml of medium at pH 4),

monitoring with a pH electrode. The kinetics is monitored for 3 hours with
sampling at times 75, 90, 120 and 180 minutes and each sample is filtered
at 5 urn and then analyzed.
• Analyses: Two methods of analysis can be used depending on the
sensitivity required and the dosage form under investigation: UV
spectrophotometry (for active principle only) or HPLC (for active principle
only or formulated).
The concentration at a time t is determined based on the previously
established calibration. During analysis by UV spectrophotometry, the
whole absorption spectrum is monitored at least at the end of the kinetic
study. In addition, the pH of the medium is monitored at the end of the
kinetic study.
OOOResults:
The dissolution kinetics of the active principle (expressed as
percentage of product released) as a function of time is plotted, first at pH 4
(simulation of the gastric medium), then at pH 6.5 (simulation of the
intestinal medium) continuously on one and the same curve shown in Fig.
1. The dissolution kinetics was measured in the same conditions for the
hard capsules G1-G7 and for the reference hard capsule, with the
compositions defined above.
The tablet shows a significant, noticeable improvement in the
percentage of active principle released relative to the reference hard
capsule but only in simulated intestinal pH conditions.
Hard capsule G3 containing dronedarone hydrochloride in a matrix
of lipid excipient without surfactant shows a significant improvement in the
percentage of active principle released relative to the reference hard
capsule or to the tablet with in addition better release in the conditions of
simulated gastric pH.
Hard capsule G1 containing dronedarone hydrochloride in a matrix
of lipid excipient in the presence of surfactant presents an improvement in
the percentage of active principle released that is very significant relative to
hard capsule G3 and relative to the reference hard capsule and the tablet.
Hard capsule G2 containing dronedarone base formed in situ in the
matrix of lipid excipient from dronedarone hydrochloride shows a very
significant improvement in the percentage of active principle released
relative to the reference hard capsule, to the tablet and to hard capsule G3.

Hard capsules G4 and G5 containing dronedarone in the form of
free base in a matrix of lipid excipient also show a very significant
improvement in the percentage of active principle released relative to the
reference hard capsule, to the tablet and to hard capsule G3, moreover
with behavior during dissolution equivalent to that of hard capsule G2.
The beneficial effect of the presence of the lipid excipient in the
formulations containing dronedarone in the base form or as hydrochloride
relative to the reference hard capsule and to the tablet, in which it is not
present, can be seen from the curves shown in Fig. 1.
Furthermore, it can be seen that there is a very marked
improvement in the percentage of active principle released for the hard
capsules that further comprise surfactant in their composition relative to the
hard capsules without it (curve for G1 vs curve for G3 and curve for G5 vs
curve for G6).
Moreover, in the case of the formulations containing dronedarone in
its base form in the matrix, the profile of the percentage of active principle
released is rapid from the very first moments in the conditions of simulated
gastric pH, in contrast to the formulation containing dronedarone
hydrochloride, whose release is observed in the best case at intestinal pH.
Effect of the proportion of Gelucire 44/14 on the base form of
dronedarone
The positive effect of increasing the proportion of Gelucire can be
seen from the curves shown in Fig. 2.
Effect of the proportion of Gelucire 44/14 on the dronedarone
hydrochloride salt
The positive effect of increasing the proportion of Gelucire can be
seen from the curves shown in Fig. 3.
Effect of the proportion of surfactant on the base form of
dronedarone

It can be seen from the curves shown in Fig. 4 that the proportion of
surfactant in a composition according to the invention does not have an
effect on the release of the active principle.
Effect of the proportion of surfactant on the dronedarone
hydrochloride salt
It can be seen from the curves shown in Fig. 5 that the proportion of
surfactant in a composition according to the invention has a beneficial
effect on release of the active principle with an optimal proportion between
10 and 30%.
Influence of the nature of the surfactant on the base form of
dronedarone and on dronedarone hydrochloride

It can be seen from the curves shown in Fig. 6 that the kinetics of
release of the base form are equivalent regardless of which nonionic
surfactant is used.
It can be seen from the curves shown in Fig. 7 that the kinetics of
release of dronedarone hydrochloride have better profiles for an HLB
between 15 and 25 and more particularly around 22.
EVALUATION OF BIOAVAILABILITY
Bioavailability refers to quantification of the absorption of the medicinal
product. It is related to the fraction of the dose of a medicinal product
administered that reaches the general circulation and to the rate at which it
reaches it. The bioavailability for oral administration depends inter alia on

digestive absorption and on the first-pass metabolism in the intestine and
the liver.
Protocol: 12 young subjects in good health receive, either on an empty
stomach or during a high-fat meal, a single dose of 400 mg BID of
dronedarone on absorbing the hard capsules G1, G2 or G3 with the
compositions defined above. Blood samples are collected regularly for 48h
and the plasma collected is tested by LC-UV methods in order to determine
the plasma concentration of dronedarone as a function of time.
Cmax, Tmax and AUC are measured on the curves thus obtained. The
results obtained are presented in Tables 4 and 5 below.
Cmax corresponds to the peak plasma concentration of
dronedarone.
tmax corresponds to the time to reach Cmax.
AUC corresponds to the area under curve or integral of plasma
concentration as a function of the time t.

* Cmax (fasting) corresponds to the ratio of the Cmax measured for a hard
capsule according to the invention absorbed by a fasting patient to the
Cmax measured for a reference hard capsule, absorbed by this same
fasting patient.
** AUC (fasting) corresponds to the ratio of the AUC measured for a hard
capsule according to the invention absorbed by a fasting patient to the AUC

measured for a reference hard capsule, absorbed by this same fasting
patient.
*** Cmax (with a meal) corresponds to the ratio of the Cmax measured for
a hard capsule according to the invention absorbed by a patient during a
meal to the Cmax measured for a reference hard capsule, absorbed by this
same patient during a meal.
**** AUC (with a meal) corresponds to the ratio of the AUC measured for a
hard capsule according to the invention absorbed by a patient during a
meal to the AUC measured for a reference hard capsule, absorbed by this
same patient during a meal.

n Cmax corresponds to the ratio of the Cmax measured for a given hard
capsule absorbed by a patient during a meal to the Cmax measured for
one and the same given hard capsule absorbed by a fasting patient.
00 Meal effect corresponds to the ratio of the AUC measured for a given
hard capsule absorbed by a patient during a meal to the AUC measured for
one and the same given hard capsule absorbed by a fasting patient.
Results:
The results indicate that in fasting conditions, the bioavailability of
hard capsules G1, G2, G3 according to the invention increases significantly
compared to the reference hard capsule, capsule G2 being the most
effective.
Furthermore, it can be seen that the meal effect decreases
significantly for the hard capsules according to the invention relative to the
reference hard capsule, capsule G2 being the one with the lowest meal
effect, of the order of 1.46.

EVALUATION OF BIOAVAILABILITY
Protocol
Treatment and administration
The dose used is 60 mg/animal regardless of the period/condition
corresponding to 6 mg/kg (assuming a weight of 10 kg for a dog) and to the
dose of 400 mg used in humans (i.e. about 6 mg/kg for a human weighing
70 kg).
The conditions of administration are as follows:
• Period while fasting: the animals are not fed in the evening preceding
dosing. Water as well as routine feed (SSNIFFhdH) are given 1 hour and 4
hours after administration, respectively.
• Period with feeding: the animals receive 50g of a high-fat diet (SSNIFF
EF Dog FDA Model high fat) 10 minutes before dosing (this diet has an
energy value of 100 kcal and is composed of 15% proteins, 25%
carbohydrates and 50-60% fat). Water and routine feed for dogs
(SSNIFFhdH) are then given 1 hour and 4 hours after administration,
respectively.
Pretreatment with pentagastrin is carried out 0.5 h before dosing.
Pentagastrin (6 ug/kg, 0.25 mL/kg) is administered intramuscularly and
makes it possible to maintain the animal's gastric pH between 2-3, thus
simulating the conditions in humans.
Administration of the capsule is followed by 30 mL of water by gavage,
which corresponds approximately to a volume of 240 mL given to a human
subject during a clinical trial.
The treatments are:
Treatment 1: 60 mg of dronedarone hydrochloride in a capsule in fasting
conditions, oral route (reference hard capsule) (ref 2)

Treatment 2: 60 mg of dronedarone hydrochloride in a capsule with
Gelucire and poloxamer 407, in fasting conditions, oral route (=G1).
Treatment 3: 60 mg of dronedarone base form reconstituted in situ from
dronedarone hydrochloride in a capsule with Gelucire and poloxamer 407,
in fasting conditions, oral route (=G2).
Treatment 4: 60 mg of dronedarone base form in a capsule with Gelucire
and poloxamer 407, in fasting conditions, oral route (= G5).
Treatment 5: 60 mg of dronedarone base form in a capsule with Gelucire
and poloxamer 407, in fed conditions, oral route (= G5).
Treatment 6: 60 mg of dronedarone base form in a capsule with Gelucire
and without poloxamer 407, in fasting conditions, oral route (=G8).
Treatment 7: 60 mg of dronedarone base form in a capsule with Gelucire
and without poloxamer 407, in fed conditions, oral route (=G8).
Samples and analyses
The blood samples are collected in plastic tubes containing lithium heparin
as anticoagulant, at the following sample collection times: before treatment
and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours after administration of each treatment.
The plasma concentration of dronedarone is determined using a method of
exploratory analysis by liquid chromatography coupled to a mass
spectrometer (LC-MS/MS). The lower limit of detection with this method for
the compounds tested is 0.5 ng/mL.
Expression of the results
The pharmacokinetic parameters are calculated from the individual
concentrations by a noncompartmental analysis using the WinNonLin 5.2.1
software (Pharsight, USA) and using the theoretical sampling times
(provided that the actual sampling times do not differ by more than 15%
from the theoretical times).
The following pharmacokinetic parameters were measured for each
treatment:

- Cmax (ng/mL): corresponds to the maximum plasma concentration
observed,
- tmax (h): corresponds to the time observed for obtaining the maximum
concentration,
- AUClast: corresponds to the area under curve or integral of the plasma
concentration as a function of the time t calculated by the trapezium
method from to up to the time corresponding to the last quantifiable
concentration.
- AUC: corresponds to the area under curve or integral of plasma
concentration as a function of time extrapolated to infinity.
- T1/2z; terminal elimination half-life
The following parameters were also evaluated:
- relative bioavailability on Cmax and AUC
- ratio of the meal effect on Cmax and AUC.
Results

All the formulations tested display a higher bioavailability than the reference
capsule with a relative bioavailability in the range from 271% to 500% in
fasting conditions.
The formulations with Gelucire with dronedarone hydrochloride and
reconstituting the base in situ (Frel=301 %) showed a higher bioavailability
than the reference capsule, as in the clinical test described above.
The formulations with Gelucire using the native base display a relative
bioavailability similar to the Gelucire formulation using dronedarone
hydrochloride and reconstituting the base in situ when compared with the
reference in fasting conditions as indicated by the coverage of the
confidence interval.
The formulations with Gelucire with or without poloxamer show a similar
relative bioavailability with a bioavailability higher by 3 to 5 compared to the
reference capsule.
Table 11- Ratio of the meal effect for the capsule with Gelucire,
dronedarone base form with poloxamer

There is a tendency for a slight decrease in Cmax of 1.4 times when the
Gelucire capsule with poloxamer is administered with high-fat feed. This
decrease is not significant as the 90% CI includes unity.
Table 12- Ratio of the meal effect for the capsule with Gelucire,
dronedarone base form without poloxamer

There is a tendency for a positive meal effect when the Gelucire capsule
without poloxamer is administered with high-fat feed. In fact Cmax is
increased by 1.9 times, AUC|ast by 1.4 times and AUC by 1.3 times.

However, this increase is not significant regarding the AUC as the 90% CI
includes unity.

CLAIMS
1. A pharmaceutical composition comprising at least one active principle
selected from (i) 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-
methylsulfonamidobenzofuran in the form of base, (ii) 2-n-butyl-3-[4-(3-di-n-
butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran in the form of
a pharmaceutically acceptable salt, characterized in that it further
comprises at least one amphiphilic lipid excipient with HLB value between 2
and 20.
2. The composition as claimed in the preceding claim, characterized in that
the 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-
methylsulfonamidobenzofuran in the form of a pharmaceutically acceptable
salt is selected from 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-
methylsulfonamidobenzofuran hydrochloride, 2-n-butyl-3-[4-(3-di-n-
butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran fumarate and
2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-
methylsulfonamidobenzofuran oxalate.

3. The composition as claimed in either one of the preceding claims,
characterized in that the active principle is selected from 2-n-butyl-3-[4-(3-
di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran in the
form of base and 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-
methylsulfonamidobenzofuran hydrochloride.
4. The composition as claimed in any one of the preceding claims,
characterized in that said composition further comprises at least one
surfactant and/or at least one co-solvent.
5. The composition as claimed in any one of the preceding claims,
characterized in that said amphiphilic lipid excipient with HLB value
between 2 and 20 has a melting point below 50°C.
6. The composition as claimed in any one of the preceding claims,
characterized in that said lipid excipient is selected from the semi-solid
substituted glycerides, the liquid substituted glycerides, the semi-solid
substituted polyoxylglycerides, the liquid substituted polyoxylglycerides and
mixtures thereof.

7. The composition as claimed in any one of the preceding claims,
characterized in that said lipid excipient is selected from the Gelucires
marketed under the brand name Gelucire® 33/01, Gelucire® 39/01,
Gelucire® 43/01, Geleol® and Peceol™, the glycerides marketed under the
name Labrafac Lipophile® WL1349, the Gelucires marketed under the
brand name Gelucire®44/14 and Gelucire®50/13, the polyoxylglycerides
marketed under the brand name Labrafil®M1944CS, Labrafil®M2125CS,
Labrafil®M2130CS and Labrasol®, the medium-chain mono- and
diglycerides marketed under the name Capmul MCM®, propylene glycol
monolaurate marketed under the name Lauroglycol® 90 and Capmul
PG12®, the caprylocaproyl macrogol-8 glycerides marketed under the
name Labrasol®, the propylene glycol caprylic acid monoester marketed
under the name Capmul® PG-8 and mixtures thereof.
8. The composition as claimed in any one of the preceding claims,
characterized in that said lipid excipient is selected from the lipid excipients
having an HLB value between 5 and 18.
9. The composition as claimed in claim 8, characterized in that said lipid
excipient is selected from the lipid excipients sold under the trade name
Capmul MCM®, Lauroglycol® 90, Capmul PG12®, Labrasol®, Gelucire®
44/14, Gelucire®50/13 and Capmul® PG-8.
10. The composition as claimed in any one of the preceding claims,
characterized in that it comprises 2-n-butyl-3-[4-(3-di-n-
butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran
hydrochloride, as active principle and/or at least one semi-solid substituted
polyoxylglyceride as lipid excipient.
11. The composition as claimed in one of the preceding claims,
characterized in that it comprises:
• 1-60 wt% of at least one active principle;
• 40-99 wt% of at least one lipid excipient;
• 0-30% of at least one compound selected from surfactants,
co-solvents, diluents, disintegrants, lubricants, organic or inorganic bases
and plasticizers,
the percentages being expressed by weight relative to the total weight of
said composition.

12. The composition as claimed in one of the preceding claims,
characterized in that it comprises:
• 1 -60 wt% of at least one active principle;
• 40-99 wt% of at least one lipid excipient,
• 0-30 wt% of at least one surfactant, and
• 0-29 wt% of at least one co-solvent;
the percentages being expressed by weight relative to the total weight of
said composition.
13. The composition as claimed in one of claims 11 or 12, characterized in
that it comprises:
• 1-50wt% of at least one active principle, advantageously
between 10 and 45%, even better between 20% and 40%;
and/or
• 45-80 wt% of at least one lipid excipient, advantageously
between 50% and 60%;
and/or
• 1-20 wt% of at least one surfactant, advantageously between
5% and 15%;
and/or
• 1 -20 wt% of at least one co-solvent, advantageously between
2 and 15%.
14. The composition as claimed in one of claims 11 to 13, characterized in
that the surfactant is hydrophilic and nonionic.
15. The composition as claimed in one of claims 11 to 14, characterized in
that the surfactant is selected from:

• ethylene oxide/propylene oxide copolymers;
• polyethoxylated castor oils;
• ethoxylated polysorbates, and
• polyethylene hydroxystearates.
16. The composition as claimed in any one of claims 11 to 15,
characterized in that the surfactant is poloxamer 407.

17. The composition as claimed in any one of claims 11 to 16,
characterized in that the co-solvent is selected from the alcoholic organic
solvents or the glycol derivatives.
18. A dosage form comprising a composition as claimed in any one of
claims 1 to 17.
19. The dosage form as claimed in claim 18, characterized in that it is a ,
capsule selected from hard capsules, soft shell capsules, enteric capsules
and modified-release capsules.

20. The dosage form as claimed in either one of claims 18 to 19,
characterized in that it is a hard capsule.
21. The dosage form as claimed in any one of claims 18 to 20,
characterized in that it contains between 50 and 500 mg of active principle,.
advantageously between 200 and 400 mg of active principle.