PREPARATIONS PHARMACEUTIQUES POUR ADMINISTRATION PAR VOIE ORALE, ET LEUR PROCEDE DE PRODUCTION

PHARMACEUTICAL PREPARATIONS FOR ORAL ADMINISTRATION AND PROCESS FOR THEIR PRODUCTION

Abrégé français

L'invention concerne des préparations pharmaceutiques pour administration par voie orale se présentant sous la forme de capsules de gélatine souple remplies de liquide. Les préparations présentées se caractérisent en ce que le principe actif est dissous dans un système monophase contenant, chaque fois par rapport au système exempt d'ingrédient actif, de 1 à 20 % en poids de polyols et/ou d'alcool benzylique pharmaceutiquement compatibles, de 1 à 20 % en poids d'un ou de plusieurs tensioactifs, de 79 à 98 % en poids d'un ou de plusieurs co-tensioactifs, moins de 5 % en poids d'éthanol et moins de 10 % en poids d'eau.

Abrégé anglais

The invention concerns pharmaceutical preparations for oral administration in
liquid-filled soft gelatin capsules. The preparations are charactacterized in
that the active substance is dissolved in a single-phase system containing, in
each case relative to the system free from active substance, between 1 and 20
wt.% pharmaceutically compatible polyols and/or benzyl alcohol, between 1 and
20 wt.% of one or a plurality of surfactants, between 79 and 98 wt.% of one or
a plurality of co-surfactants, less than 5 wt.% ethanol and less than 10 wt.%
water.

Revendications

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C L A I M S :
1. Pharmaceutical preparations for oral application in
liquid-filled soft gelatin capsules, characterized in that
the active ingredient is dissolved in a one-phase system
containing, respectively based on the system without the
active ingredient, from 1 to 20% by weight of pharmaceutically
compatible polyols and/or benzyl alcohol, from 1 to
20% by weight of one or more surfactants, from 79 to 98%
by weight of one or more co-surfactants, and less than 5
by weight of ethanol and less than 10% by weight of water,
with the exception of pharmaceutical preparations containing
3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-
benzodiazepine-3-yl)-N'-(3-methylphenyl)urea.
2. The pharmaceutical preparations according to claim 1,
characterized in that their content of polyols is from 2.5
to 12.5% by weight.
3. The pharmaceutical preparations according to claim 1 or 2,
characterized in that their content of surfactants is from
5 to 15% by weight.
4. The pharmaceutical preparations according to any of claims
1 to 3, characterized in that their content of
co-surfactants is from 79 to 90% by weight.
5. A process for making pharmaceutical preparations for oral
application in liquid-filled soft gelatin capsules,
characterized in that the active ingredient is dissolved in a
one-phase system containing, respectively based on the
system without the active ingredient, from 1 to 20% by
weight of pharmaceutically compatible polyols and/or
benzyl alcohol, from 1 to 20% by weight of one or more
surfactants, from 79 to 98% by weight of one or more

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co-surfactants, and less than 5% by weight of ethanol and
less than 10% by weight of water, and the mixture is
filled in gelatin capsules in a per se known manner, with
the exception of processes in which 3R(+)-N-(2,3-dihydro-
1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-
methylphenyl)urea is employed as the active ingredient
6. The process according to claim 5, characterized in that
the content of polyols is from 2.5 to 12.5% by weight.
7. The process according to claim 5 or 6, characterized in
that the content of surfactants is from 5 to 15% by
weight.
8. The process according to any of claims 5 to 7, characterized
in that the content of co-surfactants is from 79 to
90% by weight.

Description

CA 02238409 1998-0~-22
SMB
Pharmaceutical Preparations for Oral Application
and Process for Makinq Them
Liquid-~illed gelatin capsules for oral application are pre-
pared either as soft gelatin capsules according to the rotary
die method, or as hard gelatin capsules by metering the capsule
load through a suitable metering device into the pre-fabricated
empty capsules. The selection of the vehicle which is best
suited for the respective active ingredient is based on the
sa~ety, technical processability, physical and chemical stabil-
ity of the capsules and the effectivity of the final product.
For the active ingredients to be effective in the final prod-
uct, it is important for them to have the best possible
bioavailability after intake. In order to ensure good bioavail-
àbility, one-phase systems have proven use~ul in which the
~=~ - active ingredient is ~dissolved -and which=~do not result in
spontaneous precipitations of the active ingredient upon con-
tact with the gastro-intestinal fluids.
. .
Thus, EP-A-0 25~ 386 describes a mixture of at least 5~ of
ethanol and at least 20~ of partial glycerides. The invention
is based on the observation that ethanol as a solvent can be
filled in gelatin capsules in su~ficient concentration only i~
a sufficiently high concentration of partial glycerides is
added as a cosolvent. It is shown in the Examples of the appli-
cation that although it is possible to obtain physically stable
capsules, there is always a considerable loss of ethanol in the
load by which one is forced to compensate evaporation losses of

CA 02238409 1998-0~-22
ethanol prior to encapsulation and losses due to migration
during the drying process by appropriate production additives.
EP-A-0 152 945 describes pharmaceutical multicomponent systems
of up to 70~ of oill from 2 to 60~ of emulsifier, up to 78~ of
co-emulsifier, and optionally up to 85~ of water. The di~er-
ence between emulsifiers and co-emulsifiers, and between sur-
factants and co-surfactants, resides in the so-called HLB value
which is above or below 8; c~. page 5, lines 13 to 15. The
system described contains water and a number of auxiliaries
which are primarily suitable for dermal application. The pres-
ence of water limits the solubility of the active ingredient in
the formulation. Water further causes interactions with the
capsule shell and is thus unsuitable for the formulation of
capsules.
DE 39 27 113 Al describes an agent containing two sparingly
soluble active ingredients, namely ibuprofen and codeine,
partly dissolved and partly suspended in a system which is
exclusively composed of sur~actants having an HLB value of
greater than 8. In the encapsulation in soft gelatin capsules,
this system gives rise to problems which are somewhat reduced
by the high content of undissolved active ingredients. This--- --
system is multiphase in nature and, in addition, does not
contain any co-surfactants.
DE 36 11 467 A1 contains the active ingredient hymecromone,
partly dissolved, partly suspended in a non-crystalline form,
in a mixture of polyalkylene glycol, a surfactant and pro-
panediol. This system is multiphase in nature.
DD 298 351 A5 describes a process for the preparation of a
carrier-dependent dosage form of a medicament in which the
active ingredient is dissolved in a C3 to C6 lower polyhydric
alcohol, then transferred to a molten phase together with 1 to
3 carrier substances, and introduced in gelatin capsules ac-

CA 02238409 1998-0~-22
cording to the principle of liquid filling, the congealing of
the melt being per~ormed with a saturated organic acid. If
surfactants are used, they preferably have an HLB value of
between 10 and 50; cf claim 3. This system is unsuitable for
so~t gelatin capsules.
US 5,281,420 describes a solid dispersion of the active ingre-
dient tebufelone in a sur~actant. The HLB value is preferably
higher than 14; cf. claim 4. This system is multiphase in
nature and in addition, it is only suitable for gelatin cap-
sules.
WO 94/23733 describes a pharmaceutical formulation for oral
administration containing ciclosporine as an active ingredient
and an alkylene polyether or polyester wherein the HLB value of
the component B employed must be at least 10. According to
claim 7, this formulation is preferably prepared as hard gela-
tin capsules or in the form of a tablet. This is due to the
fact that attempts to introduce these formulations into soft
gelatin capsules have failed.
DE-A-43 22 836 describes a vehicle composition of one or more
polyglycerol fatty acid esters or~sorbitan fatty acid esters, a
pharmaceutically customary oil and a non-ionic surfactant
having an HLB value of at least 10 for the formulation of
sparingly water-solubIe active substances. Concentrations of
from 20 to 45~ of non-ionic surfactants having an HLB value of
at least 10 are preferred. Examples 2 and 3 even describe a
surfactant concentration of more than 50~. Sucker, Fuchs,
Speiser, Pharmazeutische Technologie, 2nd edition, page 342,
describe that higher proportions of surfactants result in
increased processing problems in the formation of the capsule
seam. This results in more rejects in the Lorm of open capsules
so that such high surfactant concentrations cannot be contem-
plated for the formulation of capsules.

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Therefore, it has been the object of the present invention to
provide a vehicle system for drugs which avoids the addition of
larger amounts of surfactants, which is known to interfere with
the formation of seams in soft gelatin capsules, wherein the
easily evaporating vehicle ethanol is not to be used. Primar-
ily, there is to be contained as little as possible or no water
which may interact with the capsule shell. Nevertheless, this
vehicle system is to have a high dissolving property for phar-
maceutical active ingredients and not to allow spontaneous
recrystallization of the active ingredient upon mixing with
water.
This object can now be achieved in a surprisingly simple way by
the active ingredient being dissolved in a one-phase system
containing, respectively based on the system without the active
ingredient, from 1 to 20~ by weight of pharmaceutically com-
patible polyols and/or benzyl alcohol, from 1 to 20~ by weight
of one or more surfactants, from 79 to 98~ by weight of one or
more co-surfactants, and less than 5~ by weight of ethanol and
less than 10~ by weight of water.
As the polyols, there are preferably employed the pharmaceuti-
cally useful~and safe polyols, such as glycerol, propanediol or
polyethylene glycols having a molecular weight of from 300 to
1000. They are preferably employed in amounts of between 2.5
and 12.5~ by weight, based on the solution without the active
ingredient. These polyols may further by replaced completely or
in part by benzyl alcohol.
As the surfactants, there are preferably employed block poly-
mers of polyoxyethylene and polyoxypropylene, such as Pluron-
ics~, polyoxyricinol ~atty acid esters, such as Cremophor~,
polysorbates, such as Tween~, polyoxyethylene fatty acid es-
ters, such as Myrj~, polyoxyethylene glycerol monoesters, such
as various types of the Tagat series. These surfactants are

CA 02238409 1998-0~-22
preferably employed in amounts of from 5 to 15~ by weight,
based on the mixture without the active ingredient.
As the co-surfactants, there are preferably employed partial
glycerides of saturated or unsaturated ~atty acids having a
chain length of C6 to C20. Such products are sold under the
trade marks Inwitor , Softigen , Rilanit~, Tegomuls~ and Cap-
mul~. Further use~ul are acetylated partial glycerides, such as
Myracet~, and sorbitan fatty acid esters, such as products of
the Span~ series. These substances are preferably employed in
amounts o~ ~rom 79 to 90~ by weight.
The addition of ethanol and/or water is preferably entirely
dispensed with. Nevertheless, small amounts of these solvents
are allowable without jeopardizing the good result~ At any
rate, the amounts of these solvents should be below 5~ by
weight or 10~ by weight, respectively, based on the one-phase
system.
The process according to the invention for making pharmaceuti-
cal preparations for oral application in liquid-filled soft
gelatin capsules is characterized in that the active ingredient
is dissolved in a one-phase system containing, respectively
based on the system without the active ingredient, from 1 to
20~ by weight of pharmaceutically compatible polyols and/or
benzyl alcohol, from l to 20~ by weight of one or more surfac-
tants, from 79 to 98~ by weight of one or more co-surfactants,
and less than 5~ by weight of ethanol and less than 10~ by
weight of water, and the mixture is filled in gelatin capsules
in a per se known manner.
Preferably, this system is prepared by preliminarily mixing the
components in a mixing vessel. The respective pharmaceutical
active ingredients are then dissolved in this finished solvent
system. This solution is preferably filtered and deaerated and

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then introduced in soft gelatin capsules in the usual way. This
is preferably done using the rotary die method.
The invention will be further illustrated by the following
Examples and Comparative Experiments.
Example 1 (placebo solution)
Benzyl alcohol 5
Glycerol 5
Medium chain partial glycerides (Inwitor~ 988) 80
Tween 80 10~
This mixture is further processed into soft gelatin capsules in
a per se known manner. The capsules are physically stable. In
contact with gastro-intestinal fluid, they are self-emulsi-
fying.
Comparative Example 1
Benzyl alcohol 5
Glycerol 5
Medium chain partial glycerides (Inwitor~ 988) 35
Tween$ 80 55~
The mixture of these components gave rise to serious production
problems with the filling into soft gelatin capsules. Due to
insufficient seam formation, open capsules were formed. In
contact with little water, only a coarse emulsion is formed.

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Example 2
Dextromethorphan 10
Polyethylene glycol 400 6
Ethanol 4
Tegomuls 75
Cremophor~ RH 40 5~
This mixture could be processed into soft gelatin capsules in a
per se known manner. Physically stable capsules are obtained
which are self-emulsifying in contact with gastro-intestinal
fluid.
Comparative Example 2
Dextromethorphan 10
Polyethylene glycol 400 6
Ethanol 30
Tegomuls 44
Cremophor~ RH 40 10~
Already in the production of soft gelatin capsules ~rom this
solution, a loss of 20~ of the ethanol quantity employed oc-
curred. When the soft gelatin capsules were dried, a loss of
another 35~ of the ethanol employed was observed.
These capsules had to be packaged in aluminum blister packs in
order to avoid a further loss of weight. This package does not
allow offering of the capsules to the consumer in such a way
that he may see the clear, transparent solution of the active
ingredient without opening the package.

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Example 3
Indometacin ~ 5
Inwitor 742 78
Tagat ~2
Propanediol 10~
This mixture could be ~urther processed into so~t gelatin
capsules without any problem. In contact with gastro-intestinal
fluid, a tyndallizing system was formed.
Comparative Example 3
Indometacin S~
Inwitor 742 43
Tagat ~2 20
Propanediol 15
Water 17~
In the preparation o~ so~t gelatin capsules, a massive de~orma-
tion was detected after drying, especially in the region of the
capsule seam. This can be explained in such terms that the
water contained in the load is removed by drying so that a
volume concentration results which leads to a deformation of
the capsule shell.
. .
In the ~illing of this formulation into hard gelatin capsules,
softening o~ the capsule shell ~irst occurred due to the water
content which resulted in either severe deformation of the
capsules or disrupture of the capsule wall and leaking of load
in the subsequent drying process.