UTILISATION DE COPOLYMERES BLOQUES OXYDE D'ETHYLENE - OXYDE DE PROPYLENE POUR LIMITER LA FORMATION DE MOUSSE DANS DES FORMULATIONS PHARMACEUTIQUES LIQUIDES, ET DES FORMULATIONS PHARMACEUTIQUES, ET PROCEDE POUR LEUR PREPARATION

USE OF ETHYLENE OXIDE/PROPYLENE OXIDE BLOCK COPOLYMERS FOR CONTROLLING FOAM IN LIQUID PHARMACEUTICAL FORMULATIONS, PHARMACEUTICAL FORMULATIONS, AND A PROCESS FOR THEIR PREPARATION

Abrégé anglais

HOE 86/F 121
Abstract of the disclosure
The use of ethylene oxide/propylene oxide block copolymers
for controlling foam in pharmaceutical formulations,
especially in those for parenteral administration, is
described. Also described are liquid pharmaceutical
formulations and a process for their preparation.

Revendications

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THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A liquid pharmaceutical formulation which is
capable of being used for parenteral administration which
contains ethylene oxide/propylene oxide block copolymers
for controlling foam and a cephalosporin derivative or a
penicillin derivative.
2. A liquid pharmaceutical formulation which is
capable of being used for parenteral administration which
contains polyethylene/polypropylene glycol 1800 for
controlling foam in liquid pharmaceutical formulations and
a caphalosporin derivative or a penicillin derivative.
3. A liquid pharmaceutical formulation as claimed in
claim 1 or 2 wherein the formulation contains cefpirom.
4. A liquid pharmaceutical formulation as claimed in
claim 1 or 2, wherein the formulation contains procaine
benzylpenicillin.
5. A liquid pharmaceutical formulation as claimed in
claim 1, wherein the concentration of ethylene
oxide/propylene oxide is between 0.1 to 0.00001% by weight.
6. A liquid pharmaceutical formulation as claimed in
claim 1, wherein the concentration of ethylene
oxide/propylene oxide is between 0.01 to 0.0001% by weight.
7. A liquid pharmaceutical formulation as claimed in
claim 2, wherein the concentration of
polyethylene/polypropylene glycol 1800 is between 0.1 to
0.00001% by weight.
8. A liquid pharmaceutical formulation as claimed in
claim 2, wherein the concentration of

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polyethylene/polypropylene glycol 1800 is between 0.01 to
0.0001% by weight.
9. A process for the preparation of a liquid
pharmaceutical formulation as claimed in claim 1, which
comprises application of an ethylene oxide/propylene oxide
block copolymer to the solid active compound, or
impregnation of the latter with it and subsequent
dissolution in a suitable solvent, or comprises dissolution
of the active compound in a solvent in the presence of an
ethylene oxide/propylene oxide block copolymer.
10. The process as claimed in claim 9, wherein the
ethylene oxide/propylene oxide block copolymer is
polyethylene/polypropylene glycol 1800.
11. The process as claimed in claim 9 or 10, wherein
the pharmaceutical formulations contain cefpirom.
12. The process as claimed in claim 9 or 10, wherein
the pharmaceutical formulations contain procaine benzyl-
penicillin.
13. The process as claimed in claim 9, wherein the
concentration of the ethylene oxide/propylene oxide block
copolymer is between 0.1 to 0.00001% by weight.
14. The process as claimed in claim 9, wherein the
concentration of ethylene oxide/propylene oxide block
polymer is between 0.01 to 0.0001% by weight.
15. The process as claimed in claim 10, wherein the
concentration of the polyethylene/polypropylene glycol 1800
is between 0.1 to 0.0001% by weight.

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16. The process as claimed in claim 10, wherein the
concentration of the polyethylene/polypropylene glycol 1800
is between 0.01 to 0.0001% by weight.
17. The use of ethylene oxide/propylene oxide block
copolymers for controlling foam in liquid pharmaceutical
formulations which are capable of being used for parenteral
administration and which contain a cephalosporin derivative
or a penicillin derivative.
18. The use of polyethylene/polypropylene glycol 1800
for controlling foam in liquid pharmaceutical formulations
which are capable of being used for parenteral
administration and which contain a cephalosporin derivative
or a penicillin derivative.
19. The use of ethylene oxide/propylene oxide block
copolymers for controlling foam in liquid pharmaceutical
formulations which are capable of being used for parenteral
administration and which contain cefpirom.
20. The use of ethylene oxide/propylene oxide block
copolymers for controlling foam in liquid pharmaceutical
formulations which are capable of being used for parenteral
administration and which contain procaine benzylpenicillin.
21. The use as claimed in any one of claims 17 to 20,
wherein the ethylene oxide/propylene oxide is present in a
concentration of 0.1 to 0.00001.
22. The use as claimed in any one of claims 17 to 20
wherein the ethylene oxide/propylene oxide is present in a
concentration of 0.01 to 0.0001% by weight.

Description

~ 3 ~
HOECHST AKTIENGESELLSCHAFT Dr.D/gm HOE 86/F 121
The use of ethylene oxide/propylene oxide block copoly-
mers for controlling foam in liquid pharmaceutical formu-
lations, pharmaceutical formulations, and a process for
their preparation
- _
The preparation and d;spensing of liquid pharmaceutical
formulations for parenteral administration which are prone
to foam-for~ation are difficult and always time-consuming~
There is also delay involved in preparation for adminis-
tration since it is necessary to await the collapse of
the foam.
An injec~ion solution whose surface is covered with foam
cannot be adminis~ered.
For toxicological reasons, there are problems with cus-
tomary antifoam agents for liquid pharmaceutical formula-
tions for oral administration, such as silicone oil or
octanol, as additives to formulations for parenteral use.
In addition, these additives may cause turbidity in in-
jection solutions. It has been found, surprisingly, thattraces of a surfactant of the ethylene oxide/propylene
oxide~block copolymer type effect rapid collapse of the
` foam.
Ethylene oxide/propylene oxide block copolymers are used
as weakly foaming raw materials in detergents for dish-
washing and laundering. Their properties as emulsifiers,
demulsifiers and wetting agents have been described.
However, the possibility of using them as antifoam agents
is unknown.
Thus the invention relates to the use of ethylene oxide/
propylene oxide block copolymers for controlling foam in
liquid pharmaceutical formulations, especially in those
for parenteral administration~:
The particularly preferred ethylene oxide/propylene oxide
- block copolymer is polyethylene/polypropylene glycol 1800-~

`` ~ 322~7~
-- 2
(aLso called PPG 1800). The use in formulations for
parenteral administration is particularly preferred~ The
antifoam agent must comply with the purity criteria nor-
mally required of pharmaceutical auxiliari~s.
In principle, the ethylene oxide/propylene oxide block
copolymers are suitable for controlling foam in all
liquid formulations, especially aqueous, of pharmaceuti-
cals. Of course, the medicinal agents must be compatible
with the ethylene oxide/propylene oxide block copolymers
used. Examples of suitable medicinal agents are cephalo-
sporin derivatives such as cefpirom (HR 810) and penicil-
lin derivatives such as procaine benzylpenicillin.
The invention also relates to pharmaceutical formulations
containing ethylene oxide/propylene oxide block copolymers
for controlling foam, and to a process for their pre-
paration.
The liquid formulation contains about 0.1 to 0.00001% by
weight of ethylene oxide/propylene oxide block copolymer
such as, for example, PPG 1800, preferably 0.01-0.0001%
by ~eight of PPG 1800.
The process for the preparation of the formulations com-
prises application of ethylene oxide/propylene oxide
block copolymers to the solid active compound, or impreg-
nation of the latter with the polymer or addition of the
polymer to the solvent.
Example 1
A formulation intended for injections and containing
1.23 9 of HR 810 sulfate and 0~2Z g of Na2C03 (anhydrous)
showed, after dissolution in 10 ml of water, a foam which
was stable for about 5 minutes.
~'
If a 0.0005~ strength aqueous solution of polyethylene/
polypropylene glycol 1800 is used ins~ead of water for
.
.~" ~ ' .
: - ..

" ~3~2~ ~
-- 3 --
dissolving, the foam collapses virtually immediateLy after
the dissolution.
The same effect can be achieved if approximately equiva-
lent amounts of PPG 1800 are applied to the solid com-
ponents, singly or altogether, for example by precipita-
tion in the presence of PPG 1800, by addition of PPG 1800
to the solution used for washing the precipitated solids,
or by spraying PPG 1800 solution onto the solids, follswed
by drying. It is also possible to achieve the antifoam
effect of PPG 1800 by impregnation of the primary packag-
ing (for examPle injection vials and/or injection vial
stoppers) with PPG 1800.
Example 2
It is difficult to dispense a 300,000 IU/ml procaine
benzylpenicillin suspension because foaming is excessive.
The suspension has been increased in volume by the foam
and no longer fits in the injection vials intended for
primary packaging. Addition of only 0.001% of PPG 1800
counteracts foam formation, as shown by the table below:
Table
Z5
Suspension Density ~Q/ml]
2 minutes 60 minutes
after shaking after shaking
30 without PPG 1800 1.012 1.00
addition of
0.001% PPG 1800 1.041 1.055
addition of
0.01% PPG 1800 1.053 1.058
.