COMPOSITIONS RENFERMENT UN SEL DE PROPOFOL ET UNE CYCLODEXTRINE

COMPOSITIONS COMPRISING PROPOFOL SALT AND A CYCLODEXTRIN

Abrégé français

L'invention concerne une formulation pharmaceutique contenant un complexe d'un sel de propofol et d'une cyclodextrine. L'invention permet de mettre en oeuvre du propofol dans une formulation qui peut être stockée et appliquée sans problème par voie-intra-veineuse.

Abrégé anglais

The invention relates to a pharmaceutical formulation that contains a complex of a propofol salt with a cyclodextrin. The invention makes it possible to provide propofol in a formulation that can be stored and that can be administered intravenously without problems.

Revendications

-6-
Claims
1. A pharmaceutical formulation which comprises a
complex of a propofol salt with a cyclodextrin.
2. The formulation as claimed in claim 1, characterized
in that the cyclodextrin is 2-hydroxypropyl-.beta.-cyclodextrin
(HPBCD).
3. The formulation as claimed in claim 1 or 2,
characterized in that the propofol salt is an alkali metal
salt.
4. The formulation as claimed in claim 3, characterized
in that the propofol salt is a sodium salt.
5. The formulation as claimed in any one of claims 1 to
4, characterized in that the propofol salt: cyclodextrin
molar ratio is 1:2 to 1:6.
6. The formulation as claimed in claim 5, wherein the
propofol salt: cyclodextrin molar ratio is 1:2 to 1:4.
7. The formulation as claimed in claim 6, wherein the
propofol salt: cyclodextrin molar ratio is about 1:2.
8. The formulation as claimed in any one of claims 1 to
4, characterized in that the propofol salt content of the
complex is 4 to 9% by weight.
9. The formulation as claimed in any one of claims 1 to
8, characterized in that it is an aqueous solution
suitable for injection.
10. The formulation as claimed in claim 9, characterized
in that the pH is between 7 and 11.

-7-
11. The formulation as claimed in claim 9, wherein the pH
is between 8 and 11.
12. The formulation as claimed in claim 9, wherein the pH
is between 9 and 11.
13. The formulation as claimed in claim 9, wherein the pH
is between 9 and 10.
14. The formulation as claimed in any one of claims 1 to
8, characterized in that it is a water-soluble solid.
15. The formulation as claimed in any one of claims 1 to
14 for use as an anesthetic.
16. A process for preparing a formulation as claimed in
any one of claims 1 to 13, characterized by the steps:
a) preparing an alkaline aqueous solution of the
cyclodextrin,
b) dissolving
propofol in the alkaline aqueous solution.
17. The process as claimed in claim 16, characterized in
that the dissolution of the propofol takes place under an
inert gas atmosphere.
18. The process as claimed in claim 16 or 17,
characterized in that the dissolution of the propofol
takes place over a period of from 2 to 10 h.
19. The process as claimed in claim 16 or 17, wherein the
dissolution of the propofol takes place over a period of
from 3 to 5 h.

-8-
20. The process as claimed in claim 16 or 17, wherein the
dissolution of the propofol takes place over a period of
about 4h.
21. The process as claimed in any one of claims 16 to 20,
characterized in that the solution obtained in step b) is
filtered.
22. The process as claimed in any one of claims 16 to 21,
characterized in that water is removed from the optionally
filtered solution obtained in step b).
23. The process as claimed in claim 22, wherein the water
is removed from the optionally filtered solution obtained
in step b) by freeze-drying.

Description

COMPOSITIONS COMPRISING PROPOFOL SALT
AND A CYCLODEXTRIN
The invention relates to a pharmaceutical formulation which
comprises propofol.
In pharmacy, it is a frequent problem to formulate a
pharmaceutical active ingredient such that it is administered at
the intended site of action in the desired concentration and as
efficiently as possible by means of a specific type of
application. Thus, an active ingredient intended for intravenous
application must be soluble in water to a certain extent so that
a systemic concentration in the blood can be achieved at all. On
the other hand, it must generally have a certain lipophilicity
in order, if appropriate, to be able to penetrate cell membranes
at the intended site of action. A merely readily water-soluble
active ingredient can, for example, build up a high systemic
concentration in the blood following intravenous application,
but, for example in the event of excessively low lipophilicity,
it will have low bioavailability since passage through the cell
membrane is possibly inadequate at the intended site of action.
Propofol is an intravenous anesthetic tested in clinical
practice for the first time in 1977. Propofol is a scarcely
water-soluble anesthetic active ingredient which has to be
rendered accessible to intravenous administration.
The solution of the anesthetic in a fatty emulsion (trade name
Diprivan0) was able to reduce the vein pain often observed with
i.v. administration, and so propofol was introduced into
clinical practice in 1989.
This propofol lipid emulsion comprises soybean oil, glycerol and
egg phosphatides. Vein pain upon injection is a problem that
continues to arise often. Moreover,
CA 2826513 2018-08-14

CA 02826513 2013-08-02
=
- 2 -
it can lead to serious allergic reactions. Since the
formulation as a fatty emulsion favors microbial
growth, contamination of the emulsion can lead, even
after short storage times, to sepsis after
administration.
The object of the invention is to provide a
pharmaceutical formulation of the type mentioned at the
start which permits trouble-free intravenous
administration and has the specified disadvantages to a
lesser extent, if at all.
This object is achieved by complexing propofol as salt
with a cyclodextrin. Propofol can be converted to a
salt in an alkaline medium. The propofol anion can be
complexed by a cyclodextrin. Within the context of the
invention, the term propofol salt refers to the anion
of propofol (phenolate), which can be complexed by the
cyclodextrin. In the complex according to the
invention, propofol is thus present in complexed form
as an anion.
Surprisingly, it has been found that a stable,
injectable, pharmaceutical formulation with a high
propofol concentration can be prepared in this way. The
pharmaceutical formulation according to the invention
can be provided as an aqueous solution suitable for
injection. Alternatively, it is possible, after
preparing the complex, to draw off the solvent and to
provide the complex as a storable solid. Prior to
administration, this solid is converted again to an
aqueous solution.
The pH of an aqueous solution of the complex is
preferably above 7, further preferably above 8, further
preferably above 9. Preferred upper limits for the pH
are 11 or 10. Particular preference is given to a pH

CA 02826513 2013-08-02
- 3 -
range of 8-11, further preferably 9-11, further
preferably 9-10. If the complex is provided as a
storable solid, a pH from the stated ranges is
preferably established following resolubilization in
water.
According to the invention, the cyclodextrin used for
complexing the propofol is particularly preferably
2-hydroxypropyl-beta-cyclodextrin (HPBCD). The propofol
salt used is preferably an alkali metal salt,
particularly preferably a sodium salt.
The molar ratio of propofol salt and cyclodextrin to
one another is preferably 1:2 to 1:6, further
preferably 1:2 to 1:4, further preferably about 1:2.
The propofol salt content of the complex is preferably
about 4 to 9% by weight.
The invention also provides a process for preparing a
pharmaceutical formulation according to the invention.
According to the invention, firstly an alkaline aqueous
solution of the cyclodextrin is prepared. Propofol is
added to this alkaline solution and mixed, preferably
with stirring, to the point of dissolution and
complexation. This preferably takes place under an
inert gas atmosphere. According to the invention, it is
likewise possible to establish alkaline conditions only
after the propofol has been added to the cyclodextrin.
The dissolution and complexation of propofol takes
place preferably over a period of 2 to 10 h, further
preferably 3 to 5 h, further preferably about 4 h.
According to the invention, the dissolution and
complexation process takes place essentially more
quickly than in the case of the complexation of the
phenolic form of propofol. A significantly higher

CA 02826513 2013-08-02
=
- 4 -
concentration of the propofol in the complex can also
be established.
In a further step, the solution obtained according to
the invention can be freed from remaining solids
fractions, for example filtered. Of suitability is e.g.
a filtration through a pore filter with the pore size
0.45 pm.
The solvent can be drawn off from the solution prepared
according to the invention by known and suitable
processes such as, for example, freeze-drying. The
complex is provided in this way as a storable and
resolubilizable solid.
One working example of the invention is explained
below.
The specifications of all of the materials used
correspond to the European Pharmacopeia (Ph. Eur.). The
following feed substances were used:
- propofol
- NaOH
- HPBCD
- water for injection purposes
NaOH was prepared with 60 ml of water to give a 0.01 N
NaOH solution. 12 g of HPBCD were added thereto and
dissolved with stirring. Then, 0.817 g of propofol were
added and the mixture was stirred for a further 4 h at
40-80 min-1 until the evolving propofol salt was
dissolved and complexed. The resulting solution has a
pH of 9-10.
The solution obtained was filtered through a pore
filter with a pore size of 0.45 pm. After the

. = ' . CA 02826513 2013-08-02
-5-.
filtration, the solution was lyophilized. This gave a
white powder. The complex obtained can be characterized
as follows:
Water content: 1.4% by weight
pH of a 1% strength aqueous 9.5
solution:
Propofol content (calculated as 6.5% by weight
active phenol form):
Solubility of the complex in water: 41% by weight
Resolubilization of the complex in water gives an
aqueous solution with a content of active propofol of
46 mg/ml.