Note: Descriptions are shown in the official language in which they were submitted.
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Title: PROCESS FOR PRODUCING A STERILE PREDNISOLONE GEL
Field of the Invention
The invention concerns a method of producing a prednisolone gel.
Background of the Invention
Prednisolone is a glucocorticoid, of which its anti-inflammatory effect is
about two
or three times stronger than other similar cortisones. Prednisolone is known
as an anti-
inflammatory and anti-rheumatic drug. For treating dermatological conditions
and
allergies, local application is preferred. As an anti-inflammatory and allergy
medicine,
prednisolone, to a large extent, is also used for ophthalmological purposes.
The previously used commercial preparations containing prednisolone, for
topical
application, particularly for the eyes, are either aqueous suspensions or
ointments, since
prednisolone is not sufficiently soluble in water and, therefore, must be put
in suspension
or in an ointment or suspension-ointment. The disadvantage of aqueous
suspensions of
active agents such as hormones is normally, as is known to the artisan skilled
in
pharmaceutical technology, the danger of so-called "caking," viz., the
formation of
sediment, which necessitates shaking before application of the suspension.
This agitation
of the medicine by the layperson is frequently not correctly carried out and,
therefore, an
inaccurate dosage can occur. The disadvantage of the ointment-suspension lies
in the
relatively poor compatibility on account of the particle size of the
prednisolone. Although
compliance by the patient can significantly reduce its occurrence, eye injury
on account of
sedimentation can occur. There exists, therefore, a need for prednisolone in
the form of a
gel that has good compatibility in a preparation for topical application,
especially for
application to the eye. The production of such a gel, however, is very
difficult, because a
suspension of prednisolone or its pharmaceutically acceptable ester is not
sterilizable by
means of autoclaving. Heat treatment accelerates the hydrolysis of the active
ingredient
and, moreover, presents the danger of causing undesirable crystal growth to
occur. Gels,
for example of a polyacrylate gel, are actually in principle heat
sterilizable, but for
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application to the eye, the preparation must be isotonic and isotonic agents
such as
sorbitol, glycerin, and the like tend to change color on heating. In other
words, the
ingredients in a polyacrylate gel can turn a brownish color after autoclaving,
which is not
acceptable to the patient.
European patent publication EP 0562 445 A2 discloses a gel with a viscosity of
10,000 to 50,0000 mPas, comprising a polyacrylate and a fiwther polymer or
polymeric
mixture, for application to the eye, with customary auxiliary ingredients and
optionally
with one or more known ophthalmologically active ingredients.
According to one embodiment of the present invention, there is now a method of
producing a sterile prednisolone gel that is characterized in that a sterile
polyacrylate gel is
produced, but that prednisolone or its pharmaceutically acceptable salt is
separately
sterilized and incorporated into the acrylate gel, in a suitable amount, under
aseptic
conditions. Alternatively, the sterile prednisolone or its pharmaceutically
acceptable ester
is suspended with a part of the solution, which may contain a sterile tonicity
agent, used
for the production of the polyacrylate gel, and this suspension is then
homogenously
mixed in with the separately sterilized polyacrylate gel.
It has been shown that a sterile prednisolone gel in a polyacrylate base can
be
satisfactorily produced when certain method steps are followed in its
production.
According to one embodiment of the present invention, an aqueous polyacrylate
suspension is made and then autoclaved under sterile conditions. This acrylate
suspension
is mixed with a sterile-filtrated solution of preserving agent, isotonicity
agent, and
chelating agent. After careful and thorough mixing of the starting materials,
the addition
of sterile-fi1trated caustic soda solution initiates gel formation, and the
gel is further
subjected to agitation until it is homogenous. Meanwhile the prednisolone or
its
pharmaceutically acceptable ester is sterilized. This can be accomplished by
dissolving the
active substance in a suitable amount of solvent, for example ethyl acetate,
subjecting the
solution to sterile filtration, and precipitating the active substance, for
example, through
the addition of sterile water with an anti-microbial agent under aseptic
conditions. The
microbially sterile prednisolone or its pharmaceutically acceptable ester is
then triturated
or ground to a powder with about three to ten times that amount of the gel
base. The
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remaining amount of gel is then incorporated in the concentrate by thorough
mixing. The
finished gel preparation is then conventionally decanted or drawn off under
sterile
conditions. In an alternative variation of this method, the microbially
sterile prednisolone
or its pharmaceutically acceptable ester can be, to a large extent, suspended
in a part of
the aqueous solution of the tonicity agent. The polyacrylate gel can be made
in a
conventional manner with the remaining amount of isotonic agent and separately
the
isotonic suspension of the prednisolone can be homogenously mixed with the
polyacrylate
under sterile conditions.
This sterile gel is well acceptable to the patient, because its application
does not
have the disadvantage of known ointments and is not oily. Stability has been
proven, so
that the gel has a relatively long shelf life without any change in its
physical properties. In
particular, there is no crystal growth of the active ingredient. Such a
sterile gel
preparation represents a significantly improved form of application in the
ophthalmological
field. The present invention will be further explained and illustrated by the
Example that
follows.
Example
This Example illustrates a method of making a gel according to the present
invention, although the production of larger amounts of gel may be necessary
to meet
commercial demands. In the present example, the gel is produced with water
that is
suitable for injection purposes (injection grade). To produce 500 g of
polyacrylate gel,
1.220 g of polyacrylic acid (packaged under the trademark "Carbopol 980 NF")
is
carefully suspended, with the aid of an ultrasonic apparatus, in ca. 700 ml
water and
autoclaved for 20 minutes at 121° C and 2 bar pressure. In 700 ml of
sterile injection-
grade water were then dissolved 0.050 g of benzalkonium chloride (BAK), 20.000
g
sorbitol and 0.050 g of sodium EDTA (x2H20), which was then subjected to
sterile
filtering (Sartorius~ Cellulose nitrate filter, order no. 11307-SOACN, 0.2 um)
into a
sterile vessel. The sterile-filtered salt solution was then mixed, with strong
agitation, into
the autoclaved polyacrylate suspension. Sterile water in the amount of
1958.121 g was
then added, and the solution was subjected to further agitation for 5 to 10
minute.
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Subsequently, strong sodium hydroxide in the amount of 0.465 g was dissolved
in exactly
40 g of injection-grade water. This caustic soda was then introduced drop-wise
under
agitation over a sterile filter (Millex-GS, 0.22 p.m, SLGS 025 BS der Fa.
Millipore). The
mixture was agitated until the formation of a completely homogenous gel.
A microbially sterile prednisolone acetate in the amount of 5 g was then
slowly and
carefully mixed with about 30 to $0 g of the gel. The production of the
prednisolone
acetate followed from the dissolution of the prednisolone in ethyl acetate,
sterile filtration
of the solution, and separation with water containing a bacteriocide under
sterile
conditions. After the prednisolone is accordingly suspended in the given
amount of gel,
the rest of the gel, in total 495 g, is carefully incorporated into the
initial material. All
method steps were carried out under aseptic conditions.
The prepared gel was likewise drawn off in tubes under aseptic conditions. By
an
alternative method, the microbially sterile prednisolone acetate was suspended
in a
sterile-filtrated isotonic solution of 700 ml water, 0.050 g benzalkonium
chloride, 20.000
g sorbitol and 0.050 g of disodium EDTA. This solution was then, as already
described,
incorporated, under strong agitation, in the autoclaved polyacrylate
suspension. Further
adaptation or modification of the invention, corresponding to the described
production of
sterile polyacrylate gel, falling within the scope of the following claims may
occur to the
skilled artisan.
