Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-03-13
2000-11-07
Spivack, Phyllis G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 31343
Patent
active
061437786
DESCRIPTION:
BRIEF SUMMARY
The present invention relates generally to a novel pharmaceutical composition containing a substituted benzoylbenzofuran as active principle.
In particular, the invention relates to a pharmaceutical composition for parenteral administration containing, as active principle, 2-n-butyl-3-[3,5-diiodo-4-(2-diethylaminoethoxy)benzoyl]benzofuran, also known as amiodarone, or one of the pharmaceutically acceptable salts thereof, preferably its hydrochloride.
This compound, known for its beneficial properties on the cardiovascular system, is currently widely used, in the form of its hydrochloride, as an antiarrhythmic agent and as an active principle in the fundamental treatment of coronary insufficiency.
It is available in particular in the form of a solution for parenteral administration, that is to say in the form of a concentrated injectable solution, which can be diluted down to a solution for administration by perfusion.
However, on account of its intrinsic solubility, amiodarone hydrochloride poses certain problems in the development of an injectable pharmaceutical formulation which is at the same time concentrated, stable and dilutable.
Indeed, it has been observed that the solubility of this salt in water depends highly on the temperature: at 20.degree. C. the solubility is from 0.3 to 0.5 mg/ml, whereas under hot conditions, at about 60.degree. C., it increases abruptly to in excess of 100 mg/ml.
In addition, the study of light scattering of an aqueous solution containing 50 mg/ml of this active principle shows appreciable degrees of scatter which tend to prove that, even at high concentration, colloidal structures exist, measurements of the diameters by photon correlation moreover revealing a population centred around 100 nm.
Similarly, observation of concentrated aqueous solutions of amiodarone hydrochloride phase using contrast microscopy allows a smectic-type supramolecular organization to be distinguished.
Following these observations, the theory was put forward that this solubilized active principle has a micellar, or rather bicontinuous, structure.
This aqueous "pseudo-solution" obtained by heating is fairly stable. However, if it is diluted in water, it suddenly becomes turbid below 2 mg/ml.
Study of such dilute solutions by light scattering shows, in point of fact, the sudden appearance of vesicle-type structures of large diameter (about 10,000 nm), which are responsible for the turbidity below that concentration.
During dilution, it consequently appears to be desirable to maintain this apparently supramolecular structure of bicontinuous type, which corresponds to a state of equilibrium.
Amiodarone hydrochloride, in the form of a concentrated solution (50 mg/ml) is currently marketed in 3 ml ampoules, in particular for direct injectable administration. For use in perfusion, the content of this ampoule, which corresponds to the following formulation (% by weight/volume):
______________________________________ Amiodarone hydrochloride
5%
Polysorbate 80 10%
Benzyl alcohol 2%
Water for injectable preparation 83%
______________________________________
solution, so as to reach quickly and to maintain a therapeutic blood
level.
Parenteral solutions with concentrations of less than 2 mg/ml, in particular solutions of from 0.5 to 2 mg/ml, are generally made up by dilution of injectable solutions containing 50 mg/ml of amiodarone hydrochloride as indicated above.
Thus, the administration of amiodarone hydrochloride according to this injectable formulation uses an aqueous solution of this active principle containing 100 times its solubility limit in water at room temperature. Moreover, for an administration by perfusion, the formulation in question must be diluted such that the concentration of active principle after dilution is within the very region of maximum instability of approximately between 0.5 mg/ml and 2 mg/ml, which consequently justifies the presence of a relatively high content of polysorbate 80 as stabilizer.
However, it is well known that polysorbate 80, especially at no
REFERENCES:
Gough et al., J. Cardiovasc. Pharamacol. (1982), 4(3), 375-80 (Abstract).
Ward et al., J. Parenter. Sci. Technol. (1993), 47(4), 161-5 (Abstract).
Bellamy Regine
Gautier Jean-Claude
Sanofi
Spivack Phyllis G.
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