Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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BACKGROUND OF THE INVENTION
Field of the Invention
The present invention concerns soft
gelatin capsules with a gelatin shell, at least one
plasticizer, and a capsule filling which contains
at least one pharmacologically-active substance and
a solvent, as well as processes for their
manufacture.
Description of the Prior Art
Gelatin capsules, especially soft gelatin
capsules, have become increasingly important as a
form of medication since it became feasible, in the
1930's, to manufacture them by making and filling
the capsules in one operation. Compared to other
dosage forms, they show a number of advantages.
Thus, they are odorless and tasteless, they can be
taken easily and, owing to their swelling
capability~ and water solubility, the drugs are
readily liberated in the stomach. Numerous drugs
which, on account of their sensitivity to oxidation
and to light, their thermal stability or their
hygroscopicity, may not be processed into other
medicinal ~orms, can be encapsulated without
impairment of their function.
Soft gelatin capsules serve chiefly for
the containment of liquids, i.e. oily solutions,
suspensions or emulsions. Vegetable , animal and
mineral oils, liquid hydrocarbons, ethereal oils
and also polyethylene glycols are in use as
fillings. Fats and waxes are also applied or
admixed to increase the consistency.
Polyethylene glycols are superior to
other possible filling materials for 50ft gelatin
127~3~75~
capsules in a number of ways. In contrast to oily
liquids, polyethylene glycols are mixable with
water in all proportions.
At the same time, because polyethylene
5 glycols are able to dissolve many drugs which are
sparingly soluble or insoluble in water, the use of
polyethylene glycols, with such drugs, makes
possible a particularly favorable liberation of the
active material. In many cases, sparingly water
10 soluble drugs, which have been dissolved in
polyethylene glycols and then put into soft ~elatin
capsules, are outstanding, by virtue of an
exceptionally good bio-availability of the drug.
From DE-OS 33 07 353 of the applicant,
15 soft gelatin capsules are known in which the dried
capsule shell contains 4 to 40% by weight of
sorbitol and/or sorbitan, the polyethylene glycol
used in the capsule filling for solution and
suspension of the active material is at least 50~
20 by weight of a polyethylene glycol having a mean
molecular weight of 600, and the capsule filling
contains up to 20~ by weight of glycerol and/or
propylene glycol. These soft gelatin capsules have
been remarkably successful, yet they still have the
25 disadvantage that a number of active material~ are
not sufficiently soluble in polyethylene glycol.
Consequently, large capsules are necessary for the
encapsulation of such sparingly soluble active
materials. There exists, therefore, a continuing
30 need for solvents which are able to dissolve larger
amounts of acti~-e materials and yat can be
processed into stable soft gelatin capsules.
Solvents, suitable for human consumption, such as
ethanol, propylene glycol, dimethyl acetamide~
35 lactic acid, glycerol, butanediol, and the
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polyethylene glycol ethter of tetrahhydrofurfuryl
alcohol, have been shown by the invastigations of
the applicant to be unsuitable for introduction
into soft gelatin capsules in larger quantities,
because the capsule fillings made with these
solvents cause, after a short time, softening and
deformation of the capsules produced, which
therefore are not marketable.
The reasons for these stability problems
are evidetly to be sought in the good water
miscibility and the lower molecular weight of these
solvents.
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SUMMARY OF THE INVENTION
Surprisingl~, it has now been found that
mixtures of polyethylene glycol ethers of
tetrahydrofurfurol are suitable solvents for active
materials in soft gelatin capsules, if the capsule
filling is encapsulated in a wet gelatin shell and
the capsules obtained are intensively dried for at
least 5 days, and preferably for 6 to 10 days.
After 5 to 10 days, the quantities of water which
pass from tha wet gelatin shell into the capsule
filling during encapsulation have obviously been
removed to such an extent that they, together with
the polyethylene glycol ethers of
tetrahydro~urfuryl alcohol, are no longer able,
subsequently, to soften the gelatin shell again and
enable the low molecular weight solvents to escape.
Such a long and intensive drying of soft gelatin
capsules is decidedly unusual; commonly they are
dried for only 1 to 4 days. Longer drying times
not only cause unnecessary costs, but also lead to
an undesirable hardening and embrittlement of the
capsule shell. In the inventive process, certain
amounts of the polyethylene glycol ethers of
tetrahydofurfurol apparently migrate into the
capsule shell and function there as a sotener,
counteracting the hardening and embrittlement of
the capsule shell otherwise observed on drying for
too long. These quantities of the polyethylene
glycol ethers of tetrahydrofurfurol, functioning as
a softener in the capsule shell, also lead,
however, to increased sensitivity of the inventive
capsules to atmospheric moisture, so the finished
capsules should be stored out of contact with
atmospheric moisture. However, capsules
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manufactured according to the invention and stored
with atmospheric moisturs excluded have been found
to be still completely stable after 3 years.
For the first time, therefore, the
manufacture of stable soft gelatin capsules with a
low molecular weight organic solvent, mixable with
water in all.proportions, has been successful and a
wide field of possible new applications for this
solvent has been opened up.
DETAILED DESCRIPTION OF ~HE INVENTION
The polyethylene glycol ethers of
tetrahydrofurfurol have the general formula I:
CE~2 - CH2
CH2 ~C CH2(OCH2 ,CH2)nOH
where n = 1 to 6.
In particular, mixtures in which n = 1 to 6 or in
which n = 1 and 2 are commercially available and
suitable for human consumption. Thus, the
commercial products "Glyco~urol 75" (a mixture of
mono- and di-ethylene glycol ethers in a ratio of
approximately 1 : 1, wikh a mean molecular weight
of about 168) and Tetra~lykol ~ (a mixture of
mono-ethylene glycol ether, di-ethylene glycol
ether and variable proportions of tri-, tetra- and
penta-ethylene glycol ethers, with a mean molecular
weight of about 190) are especially suitable~ A
number of sparingly soluble active materials are
substantially more soluble in these sol~ents than
in polyethylene glycol, so that soft gelatin
capsules, according to the invention which axe
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6 61368-773
substantially smaller and more pleasant to take, may be
manufactured. For example, the ~wo interesting active materials,
diazepam and nifedipine, are practically twice as soluble in the
solvent used according to the invention as in Polyethylenglycol
400.
In addition, it has been found that not only pure
mixtures of polyethylene glycol ethers of tetrahydrofurfuryl
alcohol are suitable, but also mixtures with other customary
solvents and solvent aids. In particular, up to 50% by weight of
lQ polyethylene glycol, with a molecular weight of 30Q to 600 can be
added to the polyethylene glycol ethers of tetrahydrofurfuryl
alcohol ! without changing its solubility for sparingly soluble
active materials ~oo much.
The invention therefore relates to soft gelatin capsules
with a gelatin shell, at least one plasticizer and a capsule
filling that contains at least one pharmacologically active
substance and a solvent, the solvent containing at least 50% by
weight of a mlxture of polyethylene glycol ethers o~
tetrahydrofurfuryl alcohol of the formula I as defined above.
Solvent aids and emulsifiers, which are themselves
soluble, can be added to increase the solubility of certain active
materials in the solvents and solvent mixtures used according to
the invention.
The customary plasticizers, suah as glycerol, sorbitol,
sorbitan etc. are added to the;gelatln shell.
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6a 61368-773
In addition, other customary auxiliary agents, such as a
preservative (e.g. p-aminobenzoic acid and potassium sorbate),
dyestuffs, pigments, flavorings or perfumes, can be added to the
capsule shell. Desirably, the finished capsules can subsequently
also be provided with special coatings to facilitate or improve
their application. The polyethylene glycol ethers of
tetrahydrofurfuryl alcohol, used according to the invention, are
pharmacologically and toxicologically unob~ectionable an~ are
already established to a
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considerable extent for the manufacture ofinjection solutions. In the past, the oral
application of active materials in these solvents
has not occurred because the polyethylene glycol
ethers of tetrahydrofurfuryl alcohol tastes
decidedly unpleasant. A further advantage o~ the
present invention is, therefore, that these good
solvents for many active materials have now also
become available for oral dosage forms. The
relatively small amounts of the solvents in the
capsule shell do not in any way impair the oral
application of the inventive soft gelatin capsules.
The inventive soft gelatin capsules and
the process for their manufacture are explained in
more detail in the following examples and
comparative tests.
EXAMPLE 1
S00 mg of the commercial product
Tetraglykol ~ was first, without ad~ition of
active materials or auxiliary agents, introduced
into soft gelatin capsules which were then dried at
20 degrees C and 20 to 25% relative humidity, some
for only 1 day and some for 3, 5, 8 and 10 days.
After a few weeks, the solvent escaped through the
capsule shell from those capsules that were dried
for only 1 day, so that these capsules were useless
as a commercial product. The capsules that were
dried for 3 days were stable for only 12 months.
The capsules that had been dried according to the
invention for 5, 8 or 10 days were, under the same
storage conditions, completely stable for 3 years.
Also, with 8 and 10 days drying, no embrittlement
took place.
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EXAMPLE 2
Comparative solubility investigations of the active
materials nifedipine and diazepam in
polyethylenglycol 400 and Tetraglycol R yielded
the following values, in % by weight, for the
maximum solubility at 21 degrees C:
Active material Diazepam Nifedipine
PEG 400 5.9~ 4O9%
Tetraglyco~ 11.5% 10.2%
The following recipes were prepared, corresponding
to the usual dosages o~ ni~edipine and dia2epam.
The data refer to mg/capsule.
1. Nifedipine 10.0 mg
Tetraglykol~ 110.0 m~
120.0 mg
20 2. Diazepam 5.0 mg
Tetraglykol 115.0 mg
120.0 mg
3. Diazepam ~ 5.0 mg
Tetraglykol 60.0 mg
PEG 400 50.0 mg
Glycerol 5.0 mg
120.0 mg
These solutions of active materials were formed
into oval capsules within the very small, and
therefore readily swallowed, capsule size of 2
minims and dried for 6 days in each case. On
storage, in the absence o~ atmospheric moisture,
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the capsules were completely stable, like the
capsules without the active material.
