Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 0211~279 1998-04-20
PHARMACEUTICAL PRODUCTS WITH A CONTENT OF DEXPANTHENOL
FOR TOPICAL APPLICATION
The invention relates to pharmaceutical products with
a content of dexpanthenol for topical application.
Pantothinic acid is (R-3-2,4-dihydroxy-3,3-
dimethylbutyramido~propionic acid and occurs in widespread
form in nature in both animal and vegetable material. Only
the natural R-form of pantothinic acid is biologically
effective, but the alcohol corresponding to pantothinic
acid, namely dexpanthenol, also exhibits full vitamin
effectiveness, since the alcohol can be oxidized to make
pantothinic acid in the warm-blooded organism. Since
pantothinic acid itself is an unstable, viscous, highly
hygroscopic oil, its industrial processing is difficult, so
that pharmaceutically either alcohol or salts are used,
because they are more easily prepared. Pantothinic acid
and panthenol are relatively sensitive compounds, which are
decomposed by acids, bases and heat, so that preparing them
requires special precautions.
Pantothinic acid is present in the tissue
predominately in the form of the coenzyme A, which has a
key position in metabolism. The transfer of acetyl
radicals, which has fundamental significance in metabolism,
is possible only with the aid of the coenzyme A.
Therapeutically, pantothinic acid or panthenol is given in
growth disturbances, dermatitises, degenerative changes in
the central and peripheral nervous system, in cases of
diminished antibody formation, and to promote wound
healing.
Administering dexpanthenol in the form of tablets,
ampules, solutions or ointments has been usual until now,
because the great instability of dexpanthenol makes it
difficult to produce certain forms of pharmaceutical
preparations.
CA 0211~279 1998-04-20
For topical applications, dexpanthenol is as a rule
given in ointment form, including in opthalmology. In this
field, but also in the treatment of skin defects, it is
often found that with ointments, patient's compliance is
relatively poor, since to many people the greasy bases of
the ointment feels unpleasant on the skin or on the cornea.
This is particularly true for opthalmological products,
because greasy ointments combine with the tears to make a
streaky film over the cornea and thus impair vision.
There is accordingly still a need for pharmaceutical
preparations with dexpanthenol that can be applied
topically yet do not use greasy ointment bases.
According to the invention, sterile pharmaceutical
products with a dexpanthenol content for topical
application are now proposed that are characterized in that
they contain polyacrylic acid in partially neutralized form
with a molecular weight between approximately 3 and 5
million as their vehicle.
The preparation of sterile pharmaceutical products
with a content of dexpanthenol for topical application on a
nonfat basis was unsuccessful until now, because on the one
hand dexpanthenol is unstable in heat and in an aqueous
solution the decomposition product forms 3-aminopropanol.
On the other hand, sterile filtration of polyacrylate gels
is known to be impossible. Surprisingly, it has now been
found that these difficulties can be overcome if the
preparation off such gels in performed in multiple stages.
To that end, first, a polyacrylic acid suspension is
prepared from water for injection purposes and from a
polyacrylic acid having a molecular weight between
approximately 3 and 5 million and preferably 4 million, and
this suspension is autoclaved while stirring at
approximately I20~C at an overpressure of 1 bar for a
period of 20 minutes. Parallel to this, a solution of
dexpanthenol, optionally a preservative, and a
7 9
gelatizing agent is prepared and filtered in sterile fashion
in a manner known per se. This solution is added under
aseptic conditions to the polyacrylic acid suspension.
After careful mixing, this composition is then neutralized
with sterile caustic soda, and the gel forms. The
neutralization is a critical point in the preparation,
because dexpanthenol is incompatible with acids and bases,
so that adding the neutralizing agent while stirring must be
done in highly dilute form and with immediate mixing, to
prevent decomposition. The sterile gel is finally rendered
free of bubbles by evacuation and then made up and packaged
in the usual way. Preferably, the entire preparation
process takes place in a sterile inert gas, preferably
nitrogen.
As the vehicle, polyacrylic acids in partially
neutralized form are used; the acids should have a molecular
weight in the range from approximately 3 to 5 million and
preferably 4 million. Such polyacrylic acids are available
on the market, for instance under the tradename "Carbopol~".
Neutralization of the polyacrylic acids is done in the final
preparation step preferably with highly dilute sterile
caustic soda, but instead of caustic soda as the alkali,
potassium hydroxide, alkali carbonates or amines, such as
B
~lIS~7~
c triethanolamine or diisopropanolamine, may also be used.
Whether the neutralization is done with inorganic or organic
bases is not of decisive importance, as long as they are
physiologically harmless.
The preparations according to the invention preferably
contain a preservative to make it possible for them to
be germ-free or nearly so even after being used many times.
The familiar pharmaceutically usable compounds may be
employed as preservatives, including in particular
quaternaries such as cetrimides. To trap undesired
traces of metal, a chelating agent is added to the product,
such as the disodium salt of EDTA, sodium salts of
phosphoric acids, or sodium salts of nitrilotriacetic
-3a-
~ ~B
CA 0211~279 1998-04-20
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acid. Entirely surprisingly and as yet unexplained is that
effect that a slight addition of EDTA markedly increase the
stability of dexpanthenol solutions; as various experiments
have shown, this effect is not based on the chelating of
the traces of ions of metals with a valence of two or
higher that may possibly be present, but rather appears to
ensue via some other mechanism. In any case, experiments
with the storage stability and also the thermal resistance
have shown that a slight addition of EDTA, in contrast to
other complexing agents, markedly inhibits decomposition
into 3-aminopropanol.
Adjusting the pH value of the final gel is done to a
pH of 6.8 + 0.2, so that the final gels match the
physiological pH. When used in the eye or on mucous
membranes, these gels are precisely as free of reaction as
when applied to the skin, for instance if a sterile
covering is needed in the care of skin lesions of large
surface area, such as burns.
The invention will be described in further detail
below in terms of an example:
Example
In a Becomix process system with a sterile 0.2~m
filter and a gas sterile filter, a homogeneous suspension
of 160.0 kg of water for injection purposes and 1.14 kg of
polyacrylic acid with a molecular weight of 4 million
(available on the market by the tradename "Carbopol 940")
is introduced via a fiber trap filter with a pore width of
approximately 25 to 40~m. The system is then closed and
heated. The suspension is autoclaved while stirring at
121~C and 1 bar of overpressure for 20 minutes, and finally
cooled down to room temperature, with venting taking place
via the sterilized air filter.
In the meantime, 180.0 kg of water for injection
purposes is stored beforehand in a suitable attached
container at a temperature of approximately 40~C, and 19.0
kg of dexpanthenol is dissolved in it while stirring. Some
CA 0211~279 1998-04-20
.
of this solution, approximately 10.1, is removed 38 g of
cetrimide and 38 g of the disodium of ETA ~ 2H20 are
dissolved and in it, while stirring. This partial solution
is then recombined with the main quantity of dexpanthenol
solution.
The salt solution is then added, with the aid of
sterile nitrogen as a compressed gas, via the sterile
filter to the already autoclaved polyacrylic acid
suspension. The mixture is then homogenized by stirring.
Finally, evacuation is performed multiple times, down to
0.1 bar, and venting is again done via the air filter, in
order to breakdown the foam produced.
Under sterile conditions, 581 g of sodium hydroxide is
dissolved while stirring in 19.203 kg of water for
injection purposes, producing an approximately 3~ sodium
hydroxide solution. This caustic soda is then filtered via
the sterile filter into the suspension of dexpanthenol and
polyacrylic acid, with simultaneous stirring, and the
developing gel is recirculated. The delivery of caustic
soda is done drop by drop.
The pH value of the resultant gel is determined, it
should be 6.8 + 0.2. If the pH value is below 6.6, sodium
hydroxide solution is carefully added drop by drop until
the desired value is attained. It should be taken into
account that although as a rule stirring must be done while
the alkali is added in order to avoid decomposition of the
dexpanthenol, nevertheless overly long stirring at
relatively high speed can destroy the gel structure. If a
pH over 6.6 is measured for the mixture, then replenishment
with sterile water is done up to a total weight of 380.00
kg.
The composition is then stirred once again for
approximately 15 minutes at a low agitator speed of
approximately 8 rpm and finally evacuated until the gel is
practically free of bubbles. The final gel is then made up
and packaged under sterile conditions, in a manner known
per se.
