Clear, injectable formulation of an anesthetic compound

Details Clear, injectable formulation of an anesthetic compound Clear, injectable formulation of an anesthetic compound

2000-07-18

2001-12-04

Fay, Zohrey (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

C-o-group doai

C424S422000

Reexamination Certificate

active

06326406

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a clear, injectable, pharmaceutical formulation of propofol.
BACKGROUND OF THE INVENTION
Propofol, whose chemical name is 2,6-bis-(1-methylethyl)phenol, is a known anaesthetic, largely used for general anaesthesia.
The propolol formulation which is presently on the market is a non-transparent, white, oil-in-water emulsion. Similar formulations are described, for example in U.S. Pat. No. 4,799,846 and in GB 2,298,789.
Other injectable propofol preparations have been described. More particularly, WO 96/32135 discloses a pharmaceutical composition in which propofol is used as an inclusion complex with 2-hydroxypropyl-&bgr;-cyclodextrine while WO 97/10814 discloses the use of nanodispersions of propofol to be administered by intravenous route.
SUMMARY OF THE INVENTION
The present invention is directed to an aqueous, injectable pharmaceutical composition including propofol, a pharmaceutically acceptable salt of a bile acid and a lecithin.
Another embodiment of the present invention is a process for the preparation of the aqueous, injectable pharmaceutical composition including propofol, a pharmaceutically acceptable salt of a bile acid and a lecithin. The process includes the following steps: (a) adding lecithin to an aqueous solution of the pharmaceutically acceptable salt of the bile acid, the solution having a pH from 4.5 to 6.5; (b) heating the aqueous dispersion at a temperature from 35° to 85° C. for 60 minutes; (c) adding propofol, previously heated at a temperature from 35° to 85° C. to the solution obtained in step (b) heated at a temperature from 35° to 85° C.; and (d) cooling and adding water to the final volume.
DETAILED DESCRIPTION OF THE INVENTION
It has now been found that a transparent injectable formulation of propofol may be obtained by mixing propofol with a bile acid and with a lecithin, More particularly, the formulation presents noteworthy advantages over the presently marketed formulation. Such a formulation is clear, and, hence, the presence of foreign particles, such as glass residues, fibers, undissolved substances and the like, inside the vials or bottles can be easily controlled. This feature is very important for the product safety because, in general, the ready-for-use injectable solutions and, with greater reason, those exclusively used by the intravenous route, as is the case of propofol, must not contain any foreign particles.
Furthermore, the present injectable formulation may be diluted in most of the solutions for infusion, thus allowing the anaesthetist physician to dose the drug with better precision and to administer it with a greater regularity in order to obtain a more precise and safer effect.
Another very important advantage is the fact that the present formulation is stable within a temperature range from +20 to +35° C., which is broader than the stability temperature range (+2° to +25° C.) of the presently marketed formulation. Moreover, the production of the formulation of the present invention does not require any particular or sophisticated apparatus, but it is sufficient to use normal equipment for the production of pharmaceutical formulations for injectable use.
Thus, it is another object of the present invention to provide an aqueous, injectable pharmaceutical composition comprising:
(a) propofol;
(b) a pharmaceutically acceptable salt of a bile salt; and
(c) a lecithin.
The bile salt is advantageously selected from the group consisting of glycocholic acid, cholic acid: chenodesoxycholic acid, taurocholic acid, glycochenodesoxycholic acid, taurochenodesoxycholic acid, litocholic acid, urodesoxycholic acid, dehydrocholic acid, the preferred one being glychocholic acid. The pharmaceutically acceptable salts of the bile acids may be advantageously selected from the group consisting of the sodium, potassium, calcium, magnesium or ammoniun salts. The sodium salt is preferred. Sodium glycocholate is the particularly preferred pharmaceutically acceptable salt of a bile acid.
A lecithin may be soybean lecithin or egg lecithin.
The use of a salt of a cholanic acid in admixture with lecithin for the preparation of mycellar solution of non-steroidal anti-inflammatory compounds, in order to reduce or suppress the local irritation and the hemolytic effects deriving from the parenteral administration of aqueous solutions of the drugs, is described in EP-A-280987.
In the aqueous pharmaceutical formulation of the present invention, propofol is present in an amount from 8 mg to 12 mg per 1 ml of solution, advantageously from 9 mg to 11 mg per ml of solution, preferably in an amount of 10 mg per ml of solution.
The pharmaceutically acceptable salt of the bile acid is present in the aqueous pharmaceutical formulation in an amount, referred to as the free acid, from 25 to 110 mg per 1 ml of solution, preferably from 50 to 60 mg per ml of solution, Lecithin is present in an amount from 40 to 150 mg, preferably from 70 to 80 mg per ml of solution. Soybean lecithin is the preferred lecithin.
According to an advantageous embodiment of the present invention, the aqueous, injectable pharmaceutical composition comprises: from 8 to 12 mg of propofol; from 25 to 110 mg of a bile acid, as a pharmaceutically acceptable salt thereof; and from 40 to 150 mg of a lecithin per ml of solution.
According to a particularly advantageous embodiment of the present invention, in this aqueous, injectable pharmaceutical composition, the bile acid salt is sodium glycocolate and the lecithin is soybean lecithin.
An aqueous, injectable pharmaceutical formulation comprising from 8 to 12 mg, preferable 10 mg of propofol per 1 ml of solution, from 50 to 60 mg of glycocolic acid, as sodium glycocolate per ml of solution and from 70 to 80 mg of soybean lecithin per ml of solution is particularly advantageous.
The water used in the present formulation is water for injectable preparations.
For the manufacture of the present pharmaceutical formulation, the bile acid salt may be straightforwardly used as a starting material or the free acid may be previously salified with a suitable alkalinizing agent which may be, for example, an alkaline metal hydroxide such as sodium, potassium or lithium hydroxide, an alkaline-earth metal hydroxide, such as calcium or magnesium hydroxide, a metal oxide such as magnesium or aluminum oxide, a carbonic acid salt, such as sodium or potassium carbonate, sodium or potassium bicarbonate, a phosphoric acid salt, such as sodium, potassium or calcium phosphate, for example, trisodium phosphate.
It is another object of the present invention to provide a process for the preparation of an aqueous, injectable pharmaceutical composition as mentioned above, which comprises:
(a) adding lecithin to an aqueous solution of the pharmaceutically acceptable salt of the bile acid, the solution having a pH from 4.5 to 6.5;
(b) heating the aqueous dispersion to a temperature from 35° to 85° C. for 60 minutes;
(c) adding propofol, previously heated at a temperature from 35° to 85° C., to the solution obtained in step (b), heated at a temperature from 35° to 85° C.; and
(d) cooling and adding water to reach the final volume.
More particularly, the present invention concerns a process for the preparation of an aqueous, injectable pharmaceutical composition containing propofol, a pharmaceutically acceptable salt of a bile acid and a lecithin, as illustrated above, which comprises:
(a) adding lecithin to an aqueous solution of the pharmaceutically acceptable salt of the bile acid, the solution having a pH from 4.5 to 6.5;
(b) heating the aqueous dispersion to a temperature from 35° to 85° C. until a solution is complete;
(c) adding propofol, previously heated at a temperature from 35° to 85° C., to the solution;
(d) cooling to room temperature and adding water to reach the final volume is reached; all the steps being carried out in the substantial absence of oxygen.
The expression “substantial absence of oxygen” means that the solution, during the process, should have a content of oxygen not higher than 1

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