Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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PHARMACEUTICAL COMPOSITIONS HAVING THE SHAPE OF POWDERS OF
CROSS-LINKED POLYMERS LOADED WITH DRUGS AND RELATED
PREPARATION PROCESS BY SUPERCRITICAL FLUIDS
FIELD OF THE INVENTION
s The present invention refers to pharmaceutical compositions in powder form
consisting of active substances loaded on cross-linked polymers prepared with
the
technology of the supercritical fluids.
PRIOR ART
The technology with supercritical fluids (V. Krukonis, Proc. III International
io Symposium on Supercritical Fluids, Strasbourg, Vol. 1,1, 1994; Proceedings
IV
International Symposium on Supercritical Fluids, Sendai (Japan), May, 11-14,
1997, S. Sato and K. Arai Eds.) is notably developing owing to the particular
properties of these fluids which allow a safer use of them instead of the
normal
organic solvents even in the pharmaceutical field (K. A. Larson, M. L. King,
is Biotechnol. Prog., 3, 73, 1986) in the operations of extraction and
purification (G.
Brunner, peas Extraction", Springer, Darmstadt, 1994).
Besides for these applications the properties of the supercritical fluids may
be
exploited in the processing of the materials allowing, for example, the
production
of powders having controlled granulometry (J. W. Tom, P. G. Debenedetti, J.
2o Aerosol. Sci., 22, 555, 1991 ).
Among the processed materials a particular attention has been devoted to the
polymeric materials, both for the production of micronized powders and for
their
fractionation (M. McHugh, V. Krukonis, "Supercritical Fluid Extraction",
Butterworth, Meinemann, 1994). Another particularly interesting aspect
consists of
2s the utilization of the technology with supercritical fluids for the loading
of
essentially linear polymers, with additives (C. A. Perman et al., US Patent
5,508,060; M. L. Sand, US Patent 4,598,006). In particular the importance of
the
absence of cross-linking in the polymer is pointed out (M. L. Sand, US Patent
4,598,006) in order to allow the operation of impregnation.
3o Unexpectedly, using cross-linked polymers we succeeded to load them,
reaching
reasonable loading levels, with drugs, in presence of supercritical fluids.
SUMMARY
The present invention refers to pharmaceutical compositions in powder form
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prepared by loading drugs solubilized in supercritical fluids on cross-linked
polymers.
Said compositions are prepared by:
1 ) solubilization of the drug in a supercritical fluid;
s ~ contacting the supercritical fluid containing the solubilized drug with
the cross-
linked polymer;
~ impregnation of the cross-linked polymer with the supercritical fluid
containing
the drug;
~ removal of the supercritical fluid with consequent loading of the drug in
the
io cross-linked polymer itself.
DETAILED DESCRIPTION OF THE INVENTION
The fluid, consisting of a pure component or mixture, by a pump is taken to
the
desired pressure conditions. It is sent to a first container and from this one
it is
passed through a heat exchanger in order to take it to temperature and
pressure
~s conditions higher than those at which it can be considered as
supercritical. For
example, in the case of pure components, carbon dioxide (C02) is taken to
conditions higher than 31 °C and 73.8 bar; ethylene higher than
9°C and 54.4 bar;
methane higher than -82°C and 46.0 bar; propylene higher than
92°C and 46.2
bar; nitrous oxide (NZO) higher than 36.4°C and 72.45 bar , in the case
of a
2o mixture of carbon dioxide (C02) mixed with methanol (7%) it is taken to
conditions
above 40°C and 80 bar. The supercritical fluid is then passed through
an
extractor containing the drug. At the outlet of the extractor the
supercritical fluid
stream, consisting of a pure component or mixture, containing certain amount
of
drug which solubilized at the temperature and pressure conditions fixed in
2s advance, is contacted in a reactor practically set to the same operative
conditions, with the polymer, according to a static or a dynamic process. In
the
static case a predeterminate volume of the supercritical fluid with the
solubiiized
drug is introduced in an adequate container and left to equilibrate with an
adequate quantity of polymer, for a contact time in the range between 5
minutes
3o and 72 hours, preferably between 0.25 hours and 24 hours; this
equilibration
loading step can be repeated if necessary more times. In the case of the
dynamic
process the stream of the supercritical fluid generated by the pump, at the
outlet
of the extractor, is passed through a column, of predetermined size and
length,
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containing the polymer, for a contact time between 5 minutes and 72 hours,
preferably between 0.25 hours and 24 hours. Said process embodiments, static
and dynamic, can be combined; for example after passing dynamically a given
volume of supercritical fluid with the solubilized drug through a column of
s predetermined sizes, the stream is stopped, the supercritical fluid is left
in static
contact with the polymer for a predetermined time and subsequently the stream
of
the supercritical fluid is passed again through the column. In both the
processes
the loading of the drug occurs essentially through the effect of the
partitioning of
the drug itself between the supercritical fluid and the polymer. This stage of
the
~o operation may be if necessary aided by acting on other factors assisting
the
release of the drug from the supercritical fluid. At the outlet from the
impregnation
reactor the fluid stream is passed through an absorber containing activated
carbon
or other material suitable to remove from the stream itself any trace of the,
in
case residual, drug. The fluid stream may then be brought back to the ambient
is conditions and drained or if necessary cooled, sent to a reflux receiver
and from
this one by the pump to the extractor.
The polymers according to the present invention are cross-linked hydrophilic
and
hydrophobic polymers. Among the cross-linked polymers we can mention, as an
however not exhaustive exemplification: the cross-linked polyvinyl
pyrrolidone,
2o the cross-linked sodium carboxymethyl cellulose and cross-linked sodium
starch
glycolate, among the hydrophilic ones; the cross-linked polystyrene, the cross-
linked acrylic acid and the sodium salt of cross-linked polymethyl
methacrylate
among the hydrophobic ones.
Among the drugs which may be formulated according to the invention we may
2s mention, as an however not exhaustive exemplification:
Analgesics and non steroidal antiinflammatories and their salts: sodium
diciofenac, ibuprofen, naproxen, etc.; antibactericals: amoxicillin,
cephalosporins,
etc.; antifungals and antipsoriatics: ketoconazole, griseofulvin,
itraconazole,
thioconazole, etc.; antivirals: acyclovir, gancyclovir, etc.; antineoplastics
and
3o immunosuppressives: ciclosporin, etoposide, taxole and derivatives, etc.;
anxiolytics, sedatives, hypnotics: lorazepam, oxazepam, temazepam, etc.;
sexual
hormones: medroxyprogesterone acetate, testosterone, estradiol, progesterone,
etc.; peptidic molecules having different activity: LH-RH analogues,
calcitonins,
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glutathione.
The compositions according to the present invention, contain from 0.1 to 99.9%
and preferably from 0.1 to 50% by weight of the active principle with respect
to the
polymer.
s The compositions are formulated as packets or as tables, perles pellets or
granules for pharmaceutical use.
E)CAMPLE,,$
For the illustrative aim of the invention the following examples are reported
hereinafter:
to Example No. 1
grams of polymer, cross-linked polyvinyl pyrrolidone, placed in a column of 50
cm length and 0.6 cm size, are contacted with C02 saturated with nimesulide at
160 bar and 60 C°. The flux of the incoming stream of saturated C02
expressed in
flow of liquid C02 is equal to 0.1 litres/minute. At the end of the test,
after 8 hours,
is the polymer turns out to be impregnated of nimesulide for an amount equal
to
24.47%.
Example No. 2
5 grams of polymer, cross-linked potymethyl methacrylate, placed in a column
of
50 cm length and 0.6 cm size, are contacted with C02 saturated with acyclovir
at
20 220 bar and 50 C°: the flux of the incoming stream of saturated C02
expressed in
flow of liquid C02 is equal to 0.1 litreslminute.
At the end of the test, after 24 hours, the polymer turns out to be
impregnated of
acyclovir for an amount equal to 21.2%.
Examples No. 3-6
2s 15 grams of polymeric materials (respectively physically cross-linked
polyvinyl
pyrrolidone, chemically cross-linked polyvinyl pyrrolidone, cross-linked
sodium
starch giycolate and acrylic acid cross-linked with allilic esters of sucrose)
are put
into a 200 ml reactor and contacted with C02 saturated with the drug.
The reactor is washed first with C02 and then a stream of C02 saturated with
3o different drugs (nimesulide, ketoprofen, piroxicam, cimetidine
respectively) is
introduced at 160 bar and 60 °C.
At the end of the tests, after contact times respectively of 0.5 hour, 0.25
hour, 1
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hour, 2 hours, the concentrations of drug in the polymers are 22.2; 25.6;
15.3; and
20.4% respectively.
