The present invention concerns a clear pharmaceutical aqueous emulsion composition which comprises Propofol and which allows a safe administration, particularly through intravenous injection. The invention also concerns a process for preparing this composition.
Propofol (i.e. 2,6-diisopropylphenol) is a well-known intravenous anesthetic agent which has been used in pharmaceutical aqueous emulsion compositions since the early 1980's. Because of the poor solubility of Propofol in water resulting from its lipophilic nature, intravenous formulations containing Propofol needed to be optimised in order to keep the drug dissolved in a safe composition.
The first Propofol composition which appeared on the market was an intravenous opaque and stable macro-emulsion named “Intralipid”. This composition contained triglycerides such as soybean oil, which were included at a mass fraction typically of about 10%, see e.g. the “Diprivan” compositions from Astra Zeneca Pharmaceuticals which also essentially comprise a phospholipid and glycerin.
One major drawback of such triglycerides-containing emulsions resides in their unclear nature and in the relatively large medium particle size in the emulsions—typically greater than 150 nm (nanometers)—which may lead to the formation of clots in blood capillaries and other vessels, thus rendering these triglycerides containing compositions not totally safe through intravenous injection.
In order to minimize potential side effects due to high triglycerides content, some searchers have focused their works in developing triglycerides-free formulations with the aim to obtain clear aqueous compositions, as detailed below.
Patent document U.S. Pat. No. 6,623,765 discloses in its examples a clear aqueous micro-emulsion composition comprising 1% (v/v) Propofol and at least 4.05% (w/v) of a surfactant system including at least 0.05% (w/v) of sodium laurate and at least 4% of a poloxamer (i.e. a block copolymer of ethylene oxide/propylene oxide).
Patent document WO-A-00/78301 discloses in its examples another clear aqueous micro-emulsion composition essentially comprising 1 g of Propofol and at least 5.5 g of a surfactant system including one or several poloxamer(s) and a polyethylene glycol hydroxystearate.
One major disadvantage of the compositions that were tested in these documents resides in their relatively high ratio surfactant system/Propofol, which is taught to be greater than or equal to 4.05% (w/w) in U.S. Pat. No. 6,623,765 and to 5.5% in WO-A-00/78301 which results in a risk of potential side effects after intravenous injection of these compositions.
One purpose of the present invention is to overcome this disadvantage, and this is achieved in that the Applicant has surprisingly discovered that the combination, in a surfactant system for a pharmaceutical aqueous emulsion composition comprising Propofol, of:
permits to obtain a clear composition at a ratio surfactant system/Propofol lower than 4, which was totally unexpected in the prior art with such a reduced ratio, thus minimizing any alteration phenomenon of physiological parameters such as haemolysis or risk of intolerance, after intravenous injection of this composition.
It is to be noted here that the present invention resides in the unexpected and advantageous synergistic effect of said combination of monovalent metal salt(s) of fatty acid and polyethylene glycol hydroxystearate(s), in comparison to the state of the art disclosing either such a metal salt alone (see above-mentioned document U.S. Pat. No. 6,623,765), or such a polyethylene glycol hydroxystearate alone (see above-mentioned document WO-A-00/78301).
By “clear composition”, it is to be understood in the present Specification a composition which comprises Propofol dissolved into micelles having an average size less than 60 nm (nanometers). Preferably, such a clear composition is such that said micelles have an average size less than 30 nm and, still more preferably, less than or equal to 25 nm.
According to another embodiment of the invention, said pharmaceutical composition may comprise Propofol at a mass fraction (w/w) ranging from 0.1% to 2.5% and, more preferably, ranging from 0.5% to 2.2%.
According to a still further embodiment of the invention, one should note that said pharmaceutical composition is devoid of any triglyceride, contrary to several above-mentioned compositions of the state of the art.
Preferably, the fatty acid of said at least one metal salt is a carboxylic monoacid having from 8 to 18 carbon atoms. More preferably, said fatty acid is a saturated or unsaturated aliphatic acid having from 16 to 18 carbon atoms and, still more preferably, said fatty acid is oleic acid.
Also preferably, the metal of said at least one metal salt is sodium or potassium.
According to a preferred embodiment of the invention, said at least one metal salt is sodium oleate.
Preferably, said at least one polyethylene glycol hydroxystearate has from 10 to 25 ethylene oxide units and, still more preferably, 15 ethylene oxide units.
Preferably, the mass ratio (w/w) surfactant system/Propofol may be less than or equal to 2.8 and, even more preferably, less than or equal to 2.4 thanks to said synergistic combination, which is even more unexpected taking into account the above-recited prior art, for obtaining such a clear composition, thus minimizing in an even more significant way said alteration phenomenon of physiological parameters, such as haemolysis and local tolerance.
More specifically, the mass ratio (w/w) of said at least one metal salt of a fatty acid (which is included in said surfactant system) to Propofol is advantageously less than or equal to 0.05 and, even more advantageously, less than or equal to 0.03.
One should note that such a reduced ratio metal salt(s) of a fatty acid/Propofol helps to still further minimize the risk of intolerance after injection.
According to another embodiment of the invention, the mass ratio (w/w) of said at least one polyethylene glycol hydroxystearate to said at least one metal salt of a fatty acid, which further characterizes said surfactant system, ranges from 10 to 130 and, preferably, from 40 to 100.
According to another embodiment of the invention, said composition further comprises a pharmaceutically acceptable adjuvant system at a mass ratio (w/w) adjuvant system/Propofol less than or equal to 2.6.
Advantageously, said adjuvant system comprises glycerin, which allows to adjust the tonicity of the composition.
Also advantageously, said adjuvant system further comprises ethanol, preferably at a mass ratio (w/w) ethanol/Propofol less than or equal to 1.
Still advantageously, said adjuvant system further comprises a polyethylene glycol of low molecular weight, preferably at a mass ratio (w/w) polyethylene glycol/Propofol less than or equal to 1.1.
Additionally, said adjuvant system may further comprises an acylated amino acid, which may preferably be a lipoaminoacid.
It should be understood that said adjuvant system may include other pharmaceutical approved ingredients designed to adjust pH, isotonicity, to protect the composition, to preserve or to control bacterial growth.
According to a still further embodiment of the invention, said pharmaceutical composition comprises water at a mass fraction (w/w) which is greater than 90% and, more advantageously, which may be greater than or equal to 93%.
One should note that this very high water content helps to make the composition of the invention safe, especially in order to reduce the risks of side effects during or after injection (pain, haemolysis, etc.).
According to another aspect of the invention, said pharmaceutical composition may also be administrated through subcutaneous or intramuscular injection.
A process according to the invention for preparing the above-defined pharmaceutical composition essentially comprises adding Propofol to an aqueous mixture comprising:
(i) water,
(ii) a surfactant system comprising at least one pharmaceutically acceptable monovalent metal salt of a fatty acid having from 5 to 23 carbon atoms and at least one polyethylene glycol hydroxystearate, and
(iii) an adjuvant system.
Advantageously, this process may comprise:
In this in situ embodiment of the invention, said fatty acid is first advantageously mixed with water, until a homogenous dispersion is obtained. Then sodium or potassium hydroxide are added to this dispersion and mixed therewith, until a homogenous solution containing said salt is obtained. Said polyethylene glycol hydroxystearate and said adjuvant system are subsequently mixed with this solution, until a clear homogenous solution is obtained, and Propofol is eventually added thereto and mixed until a clear homogenous solution is finally obtained.
All the following compositions were obtained thanks to traditional mixing means usually used in laboratories, and according to the following process of preparation (for 100 ml of solution), unless otherwise indicated (as in example 2):
The osmolarity was measured thanks to an Automatic Micro-Osmometer “ROEBLING type 13/13DR”.
The micelle sizes were measured thanks to a “ZetaSizer Nano” from MALVERN.
A first composition according to the invention was prepared with the following formulation, in terms of mass fractions of ingredients (w/w):
This first composition contained more than 93% of water and had an osmotic value of 300 mOsm·kg−1±10%. Moreover, it showed clear optical properties, with an average micelle size of 23 nm. Furthermore, due to its high water content, low particle size distribution and particularly due to the very reduced amount of surfactant system (ratio surfactant system/Propofol of only 2.30) which was allowed by the inventive combination of PEG hydroxystearate and sodium oleate, this first composition appeared to be particularly safe for intravenous injections.
A second composition according to the invention was prepared with the following formulation in terms of mass fractions of ingredients (w/w), this second composition only differing from the first one by the use of a fatty acid not previously formed into a salt.
This second composition was prepared according to the following process of preparation:
This second composition contained more than 93% of water and had an osmotic value of 300 mOsm·kg−1±10%. Moreover, it showed clear optical properties, with an average micelle size of 27 nm.
Furthermore, due to its high water content, low particle size distribution and particularly due to the very reduced amount of surfactant system (ratio surfactant system/Propofol of only 2.30) which was allowed by the inventive combination of PEG hydroxystearate and sodium oleate, this second composition also appeared to be particularly safe for intravenous injections.
A third composition according to the invention was prepared with the following formulation in terms of mass fractions of ingredients (w/w), the ingredients of this composition being identical to those of the first one:
This third composition essentially differed from the first one in that the ratio sodium oleate/Propofol was equal to 0.03 instead of 0.05, and in that the ratio surfactant system/Propofol was equal to 2.38 instead of 2.30.
This third composition contained more than 93% of water and had an osmotic value of 300 mOsm·kg−1±10%. Moreover, it showed clear optical properties, with an average micelle size of 26 nm.
Further, due to its high water content, low particle size distribution and very reduced amount of surfactant system (ratio surfactant system/Propofol of only 2.38) which was allowed by the inventive combination of PEG hydroxystearate and sodium oleate, this third composition also appeared to be particularly safe for intravenous injections.
One will also note that the very low ratio sodium oleate/Propofol (0.03 here) helped to still further minimize the risk of intolerance of the injected composition.
A fourth composition according to the invention was prepared with the following formulation in terms of mass fractions of ingredients (w/w), the ingredients of this composition being identical to those of the third one except that the adjuvant system of this fourth composition further included a lipoaminoacid consisting of an acetylated amino acid:
Moreover, this fourth composition essentially differed from the third one in that the ratio sodium oleate/Propofol was equal to 0.025 instead of 0.03 and in that the ratio surfactant system/Propofol was equal to 2.375 in lieu of 2.38.
This fourth composition contained more than 93% of water and had an osmotic value of 300 mOsm·kg−1±10%. Moreover, it showed clear optical properties, with an average micelle size of 30 nm.
Further, due to its high water content, low particle size distribution and very reduced amount of surfactant system (ratio surfactant system/Propofol of only 2.375) which was allowed by the inventive combination of PEG hydroxystearate and sodium oleate, this fourth composition also appeared to be particularly safe for intravenous injections.
Furthermore, one will note that the extremely low ratio sodium oleate/Propofol (equal to 0.025 here) helped to still further minimize the risk of intolerance of the composition after injection.
A fifth composition according to the invention was prepared with the following formulation in terms of mass fractions of ingredients (w/w), this composition essentially differing from the first one by the mass fraction of Propofol which was 2% instead of 1%:
Moreover, this fifth composition essentially differed from the first one in that the ratio surfactant system/Propofol was lowered to 1.775 instead of 2.30, as well as the ratio adjuvant system/Propofol which was lowered to 1.775 in lieu of 2.55.
This fifth composition contained more than 90% of water and had an osmotic value of 300 mOsm·kg−1±10%. Moreover, it showed clear optical properties, with an average micelle size of 52 nm.
Furthermore, due to its high water content, low particle size distribution and extremely reduced amount of surfactant system (ratio surfactant system/Propofol of only 1.775) which was allowed by the inventive combination of PEG hydroxystearate and sodium oleate, this fifth composition also appeared to be particularly safe for intravenous injections.
A first “witness” composition according to the known prior art was prepared with the following formulation in terms of mass fractions of ingredients (w/w), this composition only differing from said second composition of the invention in that the PEG hydroxystearate was replaced by a poloxamer “Pluronic F68/F77”:
This “witness” composition contained more than 93% of water and was an opalescent solution with an average micelle size above 200 nm.
This comparative example showed the advantageous result of the synergistic combination (metal salt of a fatty acid/PEG hydroxystearate) according to said second composition of the invention, compared to the identical metal salt combined here to another nonionic surfactant (i.e. a poloxamer) which does not lead at all to a clear emulsion at such a low ratio surfactant system/Propofol of 2.30.
A second “witness” composition according to the known prior art was prepared with the following formulation in terms of mass fractions of ingredients (w/w), this composition only differing from said first composition of the invention in that PEG hydroxystearate was replaced by a PEG stearate:
This “witness” composition contained more than 93% of water, and was an opalescent solution in which PEG-15 stearate had precipitated. The average particles size therein was above 200 nm.
This comparative example showed again the advantageous result of the synergistic combination (metal salt of a fatty acid/PEG hydroxystearate) according to said first composition of the invention, compared to the identical metal salt combined here to another nonionic surfactant (i.e. a PEG stearate) which does not lead at all to a clear emulsion at such a low ratio surfactant system/Propofol of 2.30.
A third “witness” composition according to the known prior art was prepared with the following formulation in terms of mass fractions of ingredients (w/w), this composition only differing from said first composition of the invention in that the PEG hydroxystearate was replaced by an egg lecithin:
This “witness” composition contained more than 93% of water and was an opalescent solution with an average micelle size above 200 nm.
This comparative example showed again the advantageous result of the synergistic combination (metal salt of a fatty acid/PEG hydroxystearate) according to said first composition of the invention, compared to the identical metal salt combined here to another nonionic surfactant (i.e. a lipoid) which does not lead at all to a clear emulsion at such a low ratio surfactant system/Propofol of 2.30.
A fourth “witness” composition according to the known prior art was prepared with the following formulation in terms of mass fractions of ingredients (w/w), this composition essentially differing from said first composition of the invention in that sodium oleate was replaced by a poloxamer:
This “witness” composition contained more than 93% of water and was an opalescent solution with an average micelle size above 200 nm.
This comparative example showed again the advantageous result of the synergistic combination (metal salt of a fatty acid/PEG hydroxystearate) according to instant invention, compared to the identical PEG hydroxystearate combined here to another surfactant (i.e. a poloxamer) which does not lead at all to a clear emulsion at such a low ratio surfactant system/Propofol of 2.25.
A fifth “witness” composition according to the known prior art was prepared with the following formulation in terms of mass fractions of ingredients (w/w), this composition only differing from that of comparative example 4 in that the mass fractions of PEG hydroxystearate and poloxamer were mutually inverted:
This fifth “witness” composition contained more than 93% of water and was a cloudy solution with an average micelle size above 200 nm.
This comparative example showed again the advantageous result of the synergistic combination (metal salt of a fatty acid/PEG hydroxystearate) according to instant invention, compared to the identical PEG hydroxystearate combined here to another surfactant (i.e. a poloxamer) which does not lead at all to a clear emulsion at such a low ratio surfactant system/Propofol of 2.25.
1) Haemolysis Tests Conditions:
4 dogs were treated with 6 mg/kg of Propofol using said first composition of the invention, in comparison with a marketed reference composition containing 1% Propofol sold by Schering-Plough Animal Health under the trade name Rapinovet® (this Rapinovet® composition corresponding to the qualitative and quantitative composition of the Diprivan® one for human health).
Blood samples were collected before treatment (T0) and 15 minutes after injection (T15), thus corresponding to an average concentration of approximately 1500 nanograms of Propofol per milliliter of blood.
After collecting, all the compositions were centrifuged during 10 minutes at 3200 rp·min−1 and the serum samples were collected.
The titration of haemoglobin in each of the serum samples was conducted at 340 nm with an automate “LISA 200 HYCEL” calibrated with a solution of “DATATROLDIFF HYCEL”.
2) Haemolysis Results:
Table 1 hereafter contains the haemoglobin concentrations that were obtained for each of the following serum samples:
This table shows that the composition of the invention does not significantly increase the haemoglobin value and consequently does not induce any damage on the red blood cells.
Contrary to that, this table shows that the Rapinovet® or Diprivan® composition significantly increases haemoglobin values, which consequently indicates that they could potentially damage red blood cells.
This application is a national stage application filed under 35 USC 371 of International Application No. PCT/EP2005/008739, filed Jul. 8, 2005.
Filing Document | Filing Date | Country | Kind | 371c Date |
---|---|---|---|---|
PCT/EP05/08739 | 7/8/2005 | WO | 00 | 7/10/2008 |