Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-12-15
2001-02-13
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
Reexamination Certificate
active
06187746
ABSTRACT:
The present invention relates to injectable antibacterial pharmaceutical compositions intended for the parenteral administration of quinupristine and dalfopristine, without entailing side effects of intolerance at the site of injection.
European patent application EP 248,703 describes pristinamycin I derivatives of the general formula:
as well as their combination with pristinamycin II derivatives having the structure:
Quinupristine, a derivative of pristinamycin I, and dalfopristine, a derivative of pristinamycin II, are the components of Synercid®:
Synercid® (quinupristine/dalfopristine) is an injectable 30/70 combination whose antibacterial activity, in particular on vancomycin-resistant microorganisms is cited in many publications, e.g., The Annals of Pharmacotherapy, 29, 1022-1026 (1995); and Microbial Drug resistance, 1, 223-234 (1995).
Solubilization of the isolated components quinupristine or dalfopristine can be obtained in salt form. The preparation of stabilized pharmaceutical compositions comprising the quinupristine/dalfopristine combination proved to be very difficult and was finally achieved by adding at least stoichiometric amounts of methanesulphonic acid or hydrochloric acid, and were achieved at a pH within the range of from 3.5 to 5. These compositions also optionally contain a tonicity agent and/or other pharmaceutically acceptable adjuvants.
Attempts to prepare antibacterial pharmaceutical compositions comprising dalfopristine and quinupristine in the form of other salts have been unsuccessful due to the fact that one or both of the molecules was unstable either in solution or in lyophilized form.
The injection, in particular injection by infusion, of pharmaceutical compositions comprising the quinupristine/dalfopristine combination as described above entails venous intolerance effects localized in the region of the point of injection, which are manifested by inflammatory phenomena, phlebitis, allergic reactions or formation of oedemas which can go as far as to cause total interruption of the treatment. Such a situation is extremely troublesome since Synercid® (quinupristine/dalfopristine) currently proves to be among the only known clinical treatments for treating very serious infections caused by vancomycin-resistant microorganisms.
H. Yalkowsky et al., PDA Journal of Pharmaceutical Science & Technology, 50(2), 123-128 (1996) has described the study and improvement of phlebitis caused by the administration of the cardiovascular agent dexverapamil. However, this therapeutic agent has a chemical structure which is very different from those of the streptogramin family and there is furthermore no link in its physicochemical single properties.
S. L. Gupta et al., Journal of Pharmaceutical Science & Technology, 48(2), 86-91 (1994) has described the effects of various systems in order to overcome the pain and irritation during injection caused by the antihypertensive agent Abbott 72517, among which is the use of a buffer. Pharmaceutical formulations including a buffer are also there described. However, not only is this an isolated product, rather than two combined molecules each having their particular nature, but it is also not a chemically similar structure which would allow transposition with some reasonable chances of success.
Furthermore, it has not been possible to prepare stable pharmaceutical compositions of the quinupristine/dalfopristine combination with citric acid or acetic acid.
It has now been found, and this forms the subject of the present invention, that the use of an additive, combined with the injection of the antibacterial pharmaceutical composition comprising the quinupristine/dalfopristine combination, can reduce, or even eliminate entirely, the localized side effects entailed by this combination of active principles. This occurrence is surprising, given the very different nature of each of the molecules combined and the difficulties associated with the instability of certain salts of one or the other of these molecules, e.g., the appearance of many degradation impurities, as well as the poor solubility and the instability of these active principles at certain pH values.
Thus, the additive has a protective role with respect to the venous intolerance effects entailed by the injection of the quinupristine/dalfopristine combination.
Formulations of the quinupristine/dalfopristine combination exist in liquid, lyophilized or frozen form.
The lyophilized formulations can be taken up, at the time of use, in water for injectable preparations (water fip) or in any compatible injectable medium, in particular in media such as glucose solutions, for example, an aqueous 5% glucose solution, or without any limitation being implied, with dextran solutions, polyvinylpyrrolidone solutions or polysorbate 80 solutions. According to a preferred method, the formulations are taken up in solution by passing via a concentrated solution of 50 to 250 mg/ml, preferably of about 100 mg/ml, referred to hereinbelow as the “concentrate”. This solution is diluted at the time of use in an injectable medium as described above for an administration by infusion. It is also possible to take up the lyophilizate in water fip and then to dilute the concentrate thus obtained in the desired injectable medium.
The frozen formulations can be frozen from solutions initially prepared, containing 5 to 250 mg/ml, or from diluted solutions, for the preparation of frozen bags, for example. The frozen formulations are thawed at the time of use and then diluted, if necessary.
The solutions presented in the liquid state contain 5 to 250 mg/ml of active principle. They are diluted at the time of use to concentrations ranging from 0.5 to 10 mg/ml.
The term additive is understood hereinabove to refer to a buffer solution chosen from any pharmaceutically acceptable aqueous solution buffered to acidic pH, capable of fixing the pH of the medium at a value below the pH of the blood plasma, and in particular at values at which the stability of the quinupristine/dalfopristine combination is not affected, i.e. at values which do not entail any immediate or rapid degradation of one and/or the other of the active principles. Preferably, the term additive is understood to refer to any pharmaceutically acceptable solution buffered to a pH ranging from 3 to 6.
Preferably, mention may be made of any pharmaceutically acceptable solution formed by an acid/base system in which at least one of the constituents is a pharmaceutically acceptable weak acid or weak base whose pKa is within the range of from 3 to 6, and in which the resultant pH of the system is in the region of or below the above pKa.
Even more preferably, the system can comprise one or more pharmaceutically acceptable weak organic or inorganic acids whose pKa is within the range from 3 to 6, combined with its conjugate base, with a strong base or with a weak base, or alternatively the system can comprise one or more pharmaceutically acceptable strong organic or inorganic acids, combined with at least one weak base belonging to an acid/base couple whose pKa is within the range from 3 to 6.
The acids given below (or their conjugate bases) are examples of acids which can form part of the composition of the system: citric acid, acetic acid, lactic acid, amino acids, malic acid, ascorbic acid, glutamic acid, benzoic acid, histidine, glutaric acid, propionic acid, succinic acid, formic acid, maleic acid, aspartic acid, malonic acid, gluconic acid, glucoheptonic acid, and phosphoric acid. These acids can be combined with their conjugate base, with the conjugate base of another weak acid or with sodium hydroxide. The conjugate bases of the acids mentioned above can also be combined, where appropriate, with methanesulphonic acid, hydrochloric acid, phosphoric acid or sulphuric acid.
Among these examples, given without any limitation being implied, the ones which are most particularly advantageous are citric acid, acetic acid, lactic acid, amino acids and/or the conjugate bases thereof.
According to the invention, the formulations of the quinupristine/d
Barker Nicholas Paul
Conrath Guillaume
Vacus Joel
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Rhone-Poulenc Rorer S.A.
Weddington Kevin E.
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