MXPA99010960A - Clear, injectable formulation of an anesthetic compound - Google Patents

Abstract

Aqueous, injectable pharmaceutical formulation comprising propofol, a pharmaceutically acceptable salt of a bile acid and a lecithin.

Description

CLEAR INJECTABLE FORMULATION AN ANESTHESIA COMPOUND DESCRIPTION OF THE INVENTION The present invention relates to a clear, injectable pharmaceutical formulation of propofol. Propofol, whose chemical name is 2,6-bis- (1-methylethyl) phenol is a known anesthetic, greatly used for general anesthesia. The formulation of propofol, which is present in the market, is a non-transparent, white emulsion of oil and water. Similar formulations are described, for example, in the patent of US Pat. No. 4,798,846 and in GB 2,298,789. Other injectable preparations of propofol have been described.

More particularly, WO 96/32135 discloses a pharmaceutical composition wherein propofol is used as an inclusion complex with 2-hydroxypropyl-β-cyclodextrin, while W 97/10814 describes the use of propofol nanodispersions to be administered to through the intravenous route. It has now been found that a transparent injectable formulation of propofol can be obtained by mixing d.ch propofol with a bile acid and with a lecithin. More particularly, said formulation presents important advantages with respect to the formulation currently on the market. Said formulation is c'ara and, therefore, the presence of foreign particles, such as glass debris, fibers, undissolved substances and the like, within the bottles or bottles can be easily controlled. This aspect is very important for the safety of the product since, in general, the injectable solutions of easy use and, a fortiori, those used exclusively for intravenous route, as it is the case of propofol, should not contain any foreign particles. In addition, the injectable formulation herein can be diluted in most solutions for infusion, thus allowing the anesthetist to dose the drug with better precision and administer it with a greater regularity in order to obtain a more precise effect and safer. Another very important advantage is the fact that the formulation of the present is stable within a temperature range of + 2 ° to + 35 ° C, which is wider than the scale of stability temperature (+ 2 ° + + 25 ° C) of the formulation currently on the market. In addition, the production of the formulation of the present invention does not require any particular or sophisticated apparatus, but it is sufficient to use a standard equipment for the production of pharmaceutical formulations for injectable use. Thus, it is another object of the present invention to provide an injectable, aqueous pharmaceutical composition, comprising: (a) propofol; (b) a pharmaceutically acceptable salt of a bile acid; (c) a lecithin. The bile salt is advantageously selected from the group consisting of glycolic acid, cholic acid, chenodeoxycholic acid, taurocholic acid, glycokenedeoxycholic acid, taurokenedeoxycholic acid, lithocholic acid, ursodeoxycholic acid, dehydrocholic acid, with glycocholic acid being preferred. The pharmaceutically acceptable salts of the bile acids are advantageously selected from the group consisting of the sodium, potassium, calcium, magnesium or ammonium salts. The sodium salt being preferred. The sodium glycollate is the pharmaceutically acceptable salt, particularly preferred, of a bile acid. A lecithin can be a soy lecithin with egg lecithin. The use of a salt that a coic acid in mixture with lecinn for the preparation of micellar solutions of non-steroidal anti-inflammatory compounds, in order to reduce or suppress local irritations and hemolytic effects that derive from parenteral administration or aqueous solutions in said drugs is described in EP-A-280887. In the aqueous pharmaceutical formulation of the present invention, propofol is present in an amount of 8 mg to 1 mg per 1 ml of solution, advantageously 9 mg to 11 mg per solution, preferably in an amount of 10 mg per m. 'd solution. The pharmaceutically acceptable salt of bile acid is present in said aqueous pharmaceutical formulation in an amount, referred to as the free acid, of 25 to 10 mg per 1 ml of solution, preferably 50 to 60 mg per ml of solution. The lecithin is present in an amount of 40 to 150 mg, preferably 70 to 80 mg per ml of solution. Soy lecithin is the preferred lecithin. According to the advantageous embodiment of the present invention, the injectable, aqueous pharmaceutical composition comprises: - from 8 to 12 mg of propofol; - from 25 to 110 mg of a bile acid, such as a pharmaceutically acceptable salt thereof; - from 40 to 150 mg of a lecithin, per ml of solution. According to a particularly advantageous embodiment of the present invention, in this injectable, aqueous pharmaceutical composition, said bile acid salt is sodium glycollate and said lecithin is soy lecithin. An injectable, aqueous pharmaceutical formulation comprising from 8 to 12 mg, preferably 10 mg of propcfol per 1 ml of solution, 50 mg of glycolic acid, such as sodium glycocholate, per ml of solution, and 70 to 80 mg of lecit? of soy for my solution, is particularly advantageous. The water used in the formulation herein is water for injectable preparations. For the manufacture of the pharmaceutical formulation herein, the bile acid salt can be directly used as the starting material or the free acid can be previously salified with a suitable alkalizing agent, which can be, for example, a alkali metal 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 salt of carbonic acid, such 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 injectable, aqueous pharmaceutical composition, as mentioned above, which comprises: (a) adding the lecithin to an aqueous solution of the pharmaceutically acceptable salt of bile acid, said solution having a pH of 4.5 to 6.5; (b) heating the aqueous dispersion at a temperature of 35 to 85 ° C for 60 minutes; (c) adding propofol, previously heated at a temperature of 35 to 85 ° C, to the solution obtained in step (b), heated to a temperature of 35 to 85 ° C; and (d) cool and add water to reach the final volume. More particularly, the present invention relates to a process for the preparation of a pharmaceutically injectable, aqueous composition containing a 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 bile acid, said solution having a pH of 4.5 to 6.5; (b) heating the aqueous dispersion to a temperature of 35 to 85 ° C until the solution is complete; (c) adding propofol, previously heated at the temperature of 35 to 85 ° C, to said solution; and (d) cooling to room temperature and adding water until the final volume is reached; all the steps being done in a substantial absence of oxygen. The expression "substantial absence of oxygen" means that the solution, during the process, must have an oxygen content not greater than one part per million (p.p.m.), preferably not greater than 0.5 p.p.m. As stated above in step (a) the pharmaceutically acceptable salt of bile acid, preferably sodium glycollate, can be dissolved in water as such or prepared in situ through the salification of bile acid, preferably glycocholic acid, with the selected base , preferably sodium hydroxide, in the latter case, the bile acid, preferably the glycolic acid, is added to an aqueous solution of the base, preferably sodium hydroxide, by adjusting the pH of the solution thus obtained with a pharmaceutically acceptable acid, hydrochloric acid preference, in order to make said pH compatible with an intravenous administration. Said pH is maintained at a value of 4.5 to 6.5, advantageously from 5 to 6, preferably around 5.5. Step (a) is normally performed at room temperature (20 ° + 25 ° C), but a temperature is also acceptable, higher, for example of approximately 30 ° C. The medium is advantageously maintained under substantial absence of oxygen using any technique to remove it, for example, by bubbling inert gas, preferably nitrogen, into the medium and keeping the medium under an inert atmosphere throughout the process. The oxygen content can be measured according to known methods (for example, using an oxygen-sensitive electrode) and is maintained no greater than 1 p.p.m., preferably less than 0.5 p.p.m. The lecithin, preferably soy lecithin is added under vigorous stirring, advantageously in an inert atmosphere, preferably under a stream of nitrogen. In step (b) the mixture is heated to a temperature of 35 to 85 ° C in order to obtain complete dissolution. Usually, a temperature of 35 to 60 ° C, preferably 45 to 50 ° C, is used. Since the bile acids and their salts are generally surfactants, a foam can be obtained, which dissolves if the mixture is allowed to stand, advantageously always in the substantial absence of oxygen. In step (c) in the solution thus obtained, heated to35 ° -? - 85 ° C, preferably at 55 ° - 60 ° C, propofol is added, previously heated at the same temperature, under stirring and advantageously in an inert atmosphere, preferably under a stream of nitrogen. In step (d), the clear solution thus obtained, if necessary homogenized, is used at room temperature (22 ^ 25 ° C) and diluted with water until it is reached in desired volume, preferably maintaining the oxygen concentration of the medium very low, advantageously not greater than 1 ppm, preferably less than 0.5 ppm The solution thus obtained, when subjected to the conventional operations of the pharmaceutical technique for the manufacture of injectable preparations, preferably kept in hermetically sealed containers, is ready for medical use. Preferably, the formulation according to the present invention contains oxygen at a concentration not greater than 0.5 p.p.m. In the container that contains it (bottle or bottles), the upper space contains oxygen at an amount preferably not greater than 1%.

EXAMPLE In a stainless steel reactor equipped with a heating mantle, 186 ml of water for injectable preparation was introduced and nitrogen was bubbled into it at a dissolved oxygen concentration of less than 0.5 ppm, maintaining the water temperature at approximately 25CC, after 4.8 g of sodium hydroxide was added thereto, under moderate agitation and a stream of nitrogen. Upon completion of the solution, a control of the oxygen concentration was carried out, to keep less than 0.5 ppm, then 54.6 g of glycolic acid were added quickly in one portion keeping the mixture at approximately 30 ° C under strong agitation and one atmosphere of nitrogen. After dissolution, the pH was on the scale of 10 ^ 12. After the solubilization the glycolic acid. the pH was adjusted to 5.45 - ^ - 5.5 with 1N hydrochloric acid, adding said acid slowly and keeping the solution under strong agitation and a nitrogen atmosphere (oxygen concentration less than 0.5 p.p.m.). To the sodium glycollate solution, 75.6 g of soy lecithin were slowly added, keeping the solution under vigorous stirring and a stream of nitrogen, then the suspension was heated to a temperature of 45- ^ 50aC under moderate agitation and one atmosphere of nitrogen until the formation of a huge amount of foam was observed. The solution was cooled to room temperature and allowed to stand for 18 hours under a nitrogen pressure, after which the complete solubilization of the soy lecithin was controlled. The solution was heated to 55 + 60 ° C and subjected for 10 minutes to the action of a homogenizer, under a strong current of nitrogen. An amount of 10 g of propofol, previously heated to 60 ° C, was slowly emptied into the previously obtained solution, keeping it under homogenization and a stream of nitrogen, at a temperature of 65- ^ 70 ° C. The solution was homogenized until a sample of solution, diluted in 1: 1 v / v with water for injections, was clear to the naked eye. The solution was cooled to 25 ° C by adding 610 ml of water for injections, very slowly, to the solution at a temperature of 25 ° C with a dissolved oxygen content of less than 0.5 p.p.m. Then, the solution was kept under moderate agitation and a stream of nitrogen until the content of dissolved oxygen was less than 0.5 p.p.m. Then, a vacuum was made in the reactor in order to eliminate the gas dissolved in the solution and water was added, at a volume of 1000 ml, for the injectable preparation, with a content of dissolved oxygen less than 0.5 p.p.m. The solution was kept under moderate agitation and a stream of nitrogen; the pH value was controlled in order to maintain it at 6.0- ^ 6.3 (if necessary, the value should be adjusted with 0.2% hydrochloric acid or 0.2% sodium hydroxide). The amount of dissolved oxygen was controlled and the nitrogen bubbling was continued until an oxygen concentration of less than 0.5 p.p.m was obtained. The solution was filtered in a sterile unit (class 100) through a porous membrane of 0.22 microns., Durapore® type by Millipore, previously controlled and approved for its integrity. Flasks or bottles were filled under a nitrogen atmosphere, controlling the amount of residual oxygen in the upper space of the bottle or bottle in order to keep it less than 1%.

STABILITY TESTS After the initial measurement (time 0 = T0) controls were carried out after 30 days (T 0) and after 60 days (T60) of T0) For the detection of propofol, a method was performed through HPLC performed with a reversed phase column and a detector UV The specific character and the study of linearity of response in the concentration scale of the flasks gave satisfactory results to perform the stability control in an adequate way.

EXPERIMENTAL PART MATERIALS AND METHODS Reagents - Acetonitrile for HPLC, Merck-Darmstadt - Deionized water from the "Máxima ultra puré water" equipment, Elga - Propofol Standard, Archimica - code 61005. Lot No. 95005-0-01 (purity grade: 99.8%, density: 0.955 g / ml) Standard Solutions - standard solution of propofol: in a 100 ml volumetric flask, approximately 20.0 mg , exactly heavy, of pure product were mixed with water at volume. - solutions of samples of propofol in bottles: the contents of the two bottles were emptied into a perfectly dry flask. 2 ml of liquid from the flasks was pipetted through a glass pipette, emptied into a 100 ml volumetric flask and brought to volume with water. Equipment - HPLC CM 4000, Milton Roy, equipped with - Rheodyne 7125 valve with a 10 μl loop; - UV 3100 spectromonitor detector, Milton Roy, with a variable wavelength; - Mega 2m integrator Cario Erba, with a paper speed = 0.5 cm / minute; - column: Lichrospher 100 RP-18 (125 cm x 4 mm i.d., particle size 5 μ), Merck-Darmstadt; - precolumn: RP 18, Merck - Darmstadt. Chromatographic conditions - Mobile phase: acetonitrile / water = 60:40 v / v - Flow: 1 ml / min. - Wavelength detector: 270 nm. - Average propofol elution time: 4.30- ^ 1.00.

Analytical detection For the detection of the concentration of propofol in the bottles, the standard propofol solution was analyzed by repeating the analysis four times. The solutions of the samples of propofol in bottles were analyzed immediately after the detection of the standard, repeating the analysis twice. From the comparison of the average salts traced for the propofol peaks, the concentration in mg / ml of the active principle in the solution of the steps was calculated. The results summarized in the table show that the object of solution of the present patent application remains stable and clear for a period of at least 150 days from the preparation arrow, within a wide temperature range. n.d. = not determined

Claims (17)

1. - An injectable, aqueous pharmaceutical composition, comprising: (a) propofol; (b) a pharmaceutically acceptable salt of a bile acid; (c) a lecithin.

2. A composition according to claim 1, comprising: - from 8 to 12 mg of propofol; from 25 to 110 mg of a bile acid, such as a pharmaceutically acceptable salt thereof; from 40 to 150 mg of a lecithin per ml of solution.

3. The composition according to claim 1 or 2. wherein the salt of bile acid is the sodium salt.

4. The composition according to one of claims 1 to 3, wherein the bile acid, as a pharmaceutically acceptable salt thereof, is sodium glycocholate.

5. The composition according to one of claims 1 to 4, wherein the lecithin is soy lecithin.

6. The composition according to one of claims 1 to 5, comprising from 8 to 12 mg of propofol, from 50 mg of glycolic acid, such as sodium glycocholate, and 70 to 80 mg of soy lecithin per ml of solution.

7. The composition according to claim 6 which contains 10 mg of propofol per ml of solution.

8. The composition according to claim 1, which contains 9 to 11 mg of propofol per ml of solution.

9. A process for the preparation of the injectable, aqueous pharmaceutical composition of claim 1, which comprises: (a) adding the lecithin to an aqueous solution of the pharmaceutically acceptable salt of bile acid, said solution having a pH of 4.5 to 6.5; (b) heating the aqueous dispersion at a temperature of 35c to 85 ° C for 60 minutes; (c) adding propofol, previously heated at a temperature of 35 ° to 85 ° C, to the solution obtained in step (b), heated to a temperature of 35 ° to 85 ° C; and (d) cool and add water to reach the final volume.

10. A process according to claim 9, which comprises: (a) adding the lecithin to an aqueous solution of the bile acid salt, said solution having a pH of 4.5 to 6.5; (b) heating the aqueous dispersion at a temperature of 35 ° to 85 ° C for 60 minutes until the solution is complete: (c) add propofol, previously heated at the temperature of 35 ° to 85 ° C to the solution; (d) cool to room temperature and add water until the final volume is reached; all steps being performed in the absence of substantial oxygen.

11. A process according to claim 9 or 10, wherein the salt of bile acid is sodium glycocoate.

12. A process according to claim 11, wherein the sodium glycocholate is prepared in situ.

13. A process according to any of claims 9 to 12, wherein the lecithin is soy lec? Tina.

14. A process according to any of claims 10 to 13, wherein the substantial absence of oxygen is obtained by bubbling an inert gas into the mixture

15. A process according to claim 14, wherein said inert gas It is nitrogen.

16. A process according to any of claims 10 to 15, wherein the oxygen content of the mixture is maintained no greater than 1 p.p.m.

17. A process according to claim 16, wherein said oxygen content is not greater than 0.5 p.p.m.