Stabilization of naloxonhydrochlorid

Translation of description of equivalent WO 9835679 A1

Stabilization of naloxone hydrochloride

DESCRIPTION

The present invention relates to a process for the stabilization of naloxone in solution, particularly in acidic aqueous solutions, as well as in solid or semi-solid mixtures, in particular pharmaceuticals. The invention further relates to compositions, in particular pharmaceutical forms which contain a stabilizer which the dimethyl ization of naloxone to Bisnaloxon prevented.

Naloxone, {(-) 12-allyl-7, 7a, 8, 9-tetrahydro-7, 3a-dihydroxy-4aH-8, 9c-iminoethanophenathro [4, 5-bcd] furan-5, 6H-on} is a morphine antagonist (Narcanti^® ) Of the formula

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from the group of Phenanthrenalkaloide.

Until now it is assumed that naloxone and its

Salts such as the hydrochloride are fairly stable compounds and appreciable even in acidic solutions and under the influence of radical formers such as oxygen none th decomposition (oxidation, dimerization, rearrangement, etc.) are subject.

Recent long-term studies have shown that

Naloxone, contrary to the established view of the art, a substance is, the particular tends under unfavorable conditions such as those that support the free radical formation, undesired intramolecular reactions, but can also react with impurities. The chemical process of these reactions has not yet been investigated in more detail, so that the prevention of which is for the time being must be based on empirical approaches and experiments.

It is currently believed that derivatives in a selectively extending reaction according to formula Scheme I di ere naloxone and here in particular the 2, 2 'form the -Bisnaloxon. This reaction is favored by unpublished studies in the solution additionally present, nitrogen-containing organic compounds. This dimerization is triggered probably by oxidizing substances and / or radicals, which are always present in small amounts. The spontaneously and selectively extending formation of Bisnaloxon has not been described in the literature and is especially surprising in aqueous acidic solution, since the formation of dimeric compounds related substance classes typically tion conditions rather drastic reaction and alkaline environment requires, or the use of strongly oxidizing enzymes required.

Object of the present invention is to prevent the undesired intramolecular reaction to Bisnaloxon, but also the intermolecular reactions of naloxone with Begleitstof- FEN, and therefore the naloxone and salts thereof to stabilize particularly effective as an active substance in solid and liquid medicament forms. Model reactions were initially developed (as well as the spontaneous running dimerization of naloxone) cause Bisnaloxon To achieve this object. In contrast to spontaneously occurring dimerization, the conditions under Stressbedin- usually after can be observed from a few weeks, these model reactions should proceed in the same way in the time frame of a few hours to days. In a second step, was examined how the induced side reactions can be suppressed as quantitatively as possible.

Suitable model reactions have for several hours heating hydrochloric Naloxonhydrochloridlösungen to 70 ° C, the oxidation of the solution with a dilute solution of potassium permanganate in the acidic range, the oxidation with a slurry of iron (III) oxide in hydrochloric acid solution, heating the solution in the presence of azobisisobutyronitrile, and irradiating a azobisisobutyronitrilhaltigen Naloxonhydrochloridlösung proved with intense sunlight. All reactions led initially very selectively to form Bisnaloxon in amounts of about 5 - 10%, the irradiation of the solution resulted in up to 40% Bisnaloxon. The duration of the reaction and under more severe conditions then came naturally to other conversion products of Naloxonhydrochlorids.

In the context of extensive studies, the inhibitory effect of a number of substances was examined. These substances were naloxonhydrochloridhaltigen solutions added in defined amounts and subject to the respective mixtures obtained one or more model reactions.

First, typical radical scavengers or antioxidants were used. The effectiveness of the inhibitors was determined from the delayed or unobserved formation of Bisna- Loxon tested. specially suitable HPLC methods and HPTLC methods were developed to quantify Bisnaloxon in naloxonhydrochloridhaltigen solutions.

As surprising functions already in extremely low concentrations as stabilizers effective to antioxida- proved oxidants such as sulfur dioxide, sodium sulfite, sodium bisulfite, ascorbic acid and its derivatives and tocopherol as well as its water- and fat-soluble derivatives such. B. Tocofersolan® or tocopherol acetate. But sulfite, bisulfite and hydrogen sulphites of potassium, calcium and other metals show good, dimerization inhibitory effect.

Amazingly, but also compounds were effective, whose antioxidant and scavenging effect hardly ever comes to fruition or not is known:

PHB esters, BHA, BHT, gallates, as well as lower fatty acids, such as formic, acetic, and propionic acid, fruit acids, such as malic, fumaric, lactic, citric, and tartaric acid, but also phosphoric acids such as orthophosphoric acid, Sorbin - and benzoic acid as well as their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate, lecithins, mono- and polyhydroxylated benzene derivatives, such as phenol, hydroquinone, or cresol, ethylene diamine tetraacetic acid and its salts, citraconic acid, cysteine, L-cystine, Conidendrine, Diäthylcarbonate, Methylendioxyphenole,

Cephalins, ß, ß '-Dithiopropionsäure, biphenyl and other phenyl derivatives.

Weak inhibitory are salts of nitric and nitrous acid.

The addition of the indicated inhibitors in the appropriate concentrations that can be identified quickly and reliably for each composition using the described short tests to naloxone can especially in medicinal products containing other excipients and active ingredients, excellent and safe stabilize.

The present invention therefore provides a process for the stabilization of naloxone and of its salts, especially in liquid or solid medicinal forms, characterized in that adding an organic or inorganic stabilizer in an amount which prevents the dimerization of naloxone to Bisnaloxon. Usually ranges from the stabilizers described above, an amount of 0.001 to 1 wt.% Based on the total weight of naloxone-fuel mixture, from. Particularly preferred stabilizers are sulfur dioxide, and sulfurous acid and their pharmacologically compatible salts, especially their alkali metal or alkaline earth metal salts. In preferably aqueous solutions of the stabilizer is added preferably in water-soluble form, for example as a salt. In solid or semi-solid pharmaceutical forms of stabilizer should be finely dispersed, to ensure that he and the naloxone can fully develop its protective action as closely as possible.

Another object of the invention are solid, semisolid or liquid pharmaceutical forms containing naloxone or a pharmacologically acceptable salt of naloxone, characterized in that the drug forms a the dimerization of naloxone preventing stabilizer in a concentration of 0.001 to 5% by weight, preferably 0.001 to 1 wt.%, particularly preferably 0.01 to 0.5% by weight based on the total mass of the mixture.

In the following the present invention will be explained in more detail by way of examples. However, you should limit the present invention in any way. example 1

61.15 mg naloxone hydrochloride are dissolved in 10 ml of distilled water. The solution is stored in a sealed vial at 40 ° C. These storage temperature corresponds to the prescribed in the ICH guidelines for stability testing of drugs for temperature stress stability tests. After 15 days, or 2 months of Bisnaloxongehalt the solution is determined by HPLC. Figure 2 shows that the Bisnaloxongehalt of &lt;0.01% in the feed solution has risen to 2 months to 0.2%.

example 2

61.15 mg naloxone hydrochloride are dissolved in 10 ml of distilled water. The solution is heated in a sealed vial at 70 ° C and the formation of Bisna- Loxon measured by HPLC over several days. Figure 2 shows that the content of Bisnaloxon within 9 days to about 3%, based on naloxone increases.

example 3

61.15 mg naloxone hydrochloride are dissolved in 10 ml of distilled water. It puts the solution a) 0.8 mg

Iron (III) oxide to (number 1), a solution prepared in the same manner Naloxonhydrochloridlösung sets in water, b) 0.8 mg of azobisisobutyronitrile (AIBN) (series 2) and another solution c) 0.85 mg potassium (series 3) to. The solutions are stored in sealed glass vials. The solutions a) and c) are stored at room temperature, solution b) is also stored at room temperature, in addition, the solution is but irradiated in a light cabinet with light similar to daylight. Figure 3 shows that the formation of considerable amounts of Bisnaloxon in all solutions. example 4

It provides four solutions of naloxone hydrochloride in distilled water as described in Example 1, ago. To Solution A are 10.1 mg ascorbic acid to solve B 9.8 mg sodium, added to the solution C 9, 5 mg sodium bisulfite solution and D 20.6 mg tocopherol. The solutions are packaged in sealed glass vials as described in Example 2 and several days heated to 70 ° C. By means of chromatographic methods is determined the formation of Bisnaloxon. Figure 4 shows that the substances mentioned all have an inhibiting effect. Maybe this is fertilize when ascorbic acid due to the known pH and temperature instability of the substance here less pronounced than with the other compounds used.

This example demonstrates that the proposed substances are able to prevent the formation of acid in Bisnaloxon Naloxonhydrochloridlösungen.

example 5

It provides four solutions of naloxone hydrochloride in distilled water as described in Example 1, ago. Among the solutions are employed respectively as much sodium to that result from solutions containing 0.001% by weight bisulfite (= solution E), 0.01% bisulfite (= solution F), 0.1% by weight bisulfite (= solution G) and 1 wt% bisulfite (= solution H) included. Subjecting these solutions to that in Example 3 mentioned under c) a model reaction, that is, the oxidation with small amounts of potassium permanganate at room temperature. Figure 5 shows that a varying degrees of inhibitory effect can be detected depending on the concentration of bisulfite. Bisulfitkonzentrationen around and below 0.01% inhibit in this model reaction only weakly or not at all, about 0.01% against significantly. example 6

It provides four solutions of naloxone hydrochloride in distilled water, as mentioned in Example 1, ago. Among the solutions they are each so much sodium that result from solutions containing 0.001% by weight bisulfite (= solution I), 0.01% bisulfite (= solution K), 0.1% by weight bisulfite (= solution L) and 0 , 2 wt% bisulfite (= solution M) included. Subjecting these solutions the model reaction described in Example 2, that heats the solutions for several days at 70 ° C. Figure 6 shows that in all Bisulfitkonzentrationen an inhibitory effect can be detected, which is less pronounced, but has been used in each case, depending on the concentration of bisulfite.