Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-01
2003-12-16
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06664284
ABSTRACT:
The object of the invention are ready-to-inject, aqueous injection solutions containing carvedilol (1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanol) or its pharmacologically harmless salts as well as a process for their production. The injection solutions are stable on storage and are tolerated well by veins.
Carbazol-4-yloxy-propanolamine derivatives as well as their pharmacologically harmless salts, which exhibit vasodilating and &bgr;-receptor blocking activities in pharmacological tests and which are suitable for the treatment and prophylaxis of circulatory and cardiac disorders such as hypertension and angina pectoris, are known from EP 0 004 920.
Carvedilol and carvedilol derivatives are also described by Yue et al. in “The Journal of Pharmacology and Experimental Therapeutics” 236 (1), pages 92-98 (1992). The authors report that carvedilol and especially carvedilol derivatives which are hydroxylated in the carbazole structure or in the phenoxy ring exhibit an antioxidative activity and inhibit lipid peroxidation.
Although enteral, parenteral and oral dosage forms are proposed in EP 0 004 920, only oral dosage forms have hitherto been developed successfully. There has, indeed, been a series of experiments to incorporate carvedilol into conventional injectable preparations. However, these have hitherto surprisingly come to nothing. It has been found that such preparations are either not tolerated by veins or are not sufficiently stable, so that in the case of lengthy storage the solutions recrystallize or decomposition products are formed. These negative phenomena thus exclude use for injection purposes.
The solubility of carvedilol in water is about 0.2 mg/100 ml, i.e. 0.002 mg/ml, with a pH value of 6.1 resulting. This solubility is, of course, not sufficient to achieve the therapeutically required dosage of an injection solution in the order of several mg/ml. Upon standing, supersaturated solutions precipitate carvedilol crystals after a short period, so that they are unsuitable as ready-to-inject injection solutions. An increase in the acidity to pH values of 1 to 3 indeed prevents the crystallization of the carvedilol and increases the dissolved amount of the active substance, but leads to an intolerance of the solutions by veins. Moreover, decomposition products form therefrom after a short period. These decomposition products also mean that such a solution can not be used for injection purposes.
Long-term medication with carvedilol has accordingly hitherto been carried out predominantly in the form of solid dosage forms such as tablets and capsules. It would, however, also be desirable, especially for clinical uses, to provide readily injectable dosage forms. In order, in use, not to have to rely on the necessity of firstly mixing the components with one another, e.g. in the case of a lyophilizate, such an injection solution should be as “ready-to-inject” as possible. In other words, all required components should already be present in the correct ratios in the ampoule solution.
The object of the invention was to find a formulation in order to provide carvedilol or its pharmacologically harmless salts as injection solutions having therapeutically relevant concentrations, with the injection solutions being stable on storage and being tolerated well by veins.
Surprisingly, stable, vein-tolerable and high dosage injection solutions containing carvedilol or its pharmacologically harmless salts are obtained when on the one hand a physiologically compatible acidic buffer having a pH value between 7.2 and 4.0 and on the other hand an organic solvent, such as, for example, polyethylene glycol, is added to the solution. It is also necessary to add an antioxidant and an agent which binds metal ions.
The ready-to-inject injection solutions containing carvedilol or its pharmacologically harmless salts in accordance with the invention contain a physiologically compatible buffer having a pH value of 7.2 to 4.0, a water-soluble organic solvent, an antioxidant as well as an agent which binds heavy metals.
The carvedilol concentration in the ready-to-inject injection solutions is preferably 1 to 5 mg/ml.
Examples of pharmacologically harmless salts are salts of carvedilol with inorganic or organic acids, such as e.g. hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, acetic acid, citric acid, maleic acid or benzoic acid.
The injection solutions in accordance with the invention have a pH value of 4.0 to 7.4, preferably from 4.4 to 7.0.
Amounts of active substance and adjuvants are chosen such that isotonic injection solutions are obtained as far as possible. In the event that this is not already guaranteed by the available components, other adjuvants which are customary for this purpose, such as e.g. sodium chloride, fructose, glucose etc., can also be added to adjust the isotonicity.
Organic solvents which are preferably used are ethanol and solvents which have a degree of polymerization. Solvents which have a degree of polymerizaton in accordance with the invention are preferably trimethylene glycol and polyethylene glycol. Polyethylene glycol with a molecular weight between 100 and 1,500, particularly 200 to 600, has been found to be especially preferred. The organic solvent is usually added in an amount of 5 to 25 wt. %, with an addition of about 10 wt. % being preferred.
Physiologically compatible buffer substances in accordance with the invention are, for example, weak acids, such as acetic acid, malic acid, carbonic acid, phosphoric acid or amino acids. In particular, the sodium, potassium or ammonium salts of the acids such as the acetate, malate, carbonate, phosphate, glycinate, arginate or other amino acid salts come into consideration.
A special case of buffering comprises adding a further active substance which acts as a buffer to the aforementioned buffers. As the carvedilol injection solutions in accordance with the invention are stable in the acidic to neutral range, there exists the possibility of incorporating a loop diuretic in the formulations in addition to the &bgr;-blocker carvedilol. Torasemide, azosemide and furosemide are preferably used as loop diuretics, and in these aqueous injection solutions the organic solvents such as polyethylene glycol, trimethylene glycol or ethanol can be present in a maximum amount of 25%. The solubility of the loop diuretics in these acidic to maximum neutral formulations is as follows:
Torasemide from 1 mg/ml to 2 mg/ml
azosemide from 1 mg/ml to 3 mg/ml
furosemide from 1 mg/ml to 5 mg/ml
The furosemide, torasemide or azosemide is preferably added in the form of the sodium or potassium salt.
Preferred buffer substances present in the ready-to-inject injection solutions are sodium, potassium or ammonium salts of weak acids and/or loop diuretics or their sodium or potassium salts, with torasemide, azosemide or furosemide being especially preferred as the loop diuretic.
As the antioxidant there can be used any additive which is effective in an acidic medium and which is suitable for injection solutions, e.g. inorganic or organic sulphur compounds, such as e.g. methionine or sodium disulphide, or ascorbic acid in the form of sodium ascorbate. Methionine is preferably used in accordance with the invention, especially in a concentration of 1 to 10 mg/ml, preferably of 2 to 5 mg/ml.
The optimal stabilization of the formulation is guaranteed surprisingly by an agent which binds heavy metal ions, such as e.g. a complex former which inactivates heavy metal ions, preferably EDTA (ethylenediaminetetraacetic acid, edetic acid) or its disodium salt (Titriplex III). It has surprisingly been found that the solvent-containing carvedilol solutions are only sufficiently stable and endure a sterilization for 20 minutes in the final container at 121° C. without decomposition when the combination of antioxidant and heavy metal ion binder is guaranteed. The concentration of the complex former is 0.1 to 10 mg/l, preferably 0.1 to 0.3 mg/ml.
In a preferred embodiment of the invention inject
Gruber Werner
Woog Heinrich
Johnston George W.
Lau Bernard
Rocha-Tramaloni Patricia S.
Roche Diagnostics GmbH
Spivack Phyllis G.
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