DE29719704U1 - Stable preparations of naloxone hydrochloride - Google Patents

Description

The utility model relates to mixtures of substances, in particular pharmaceutical forms, which contain a stabilizer that prevents the dimerization of naloxone to bisnaloxone in solutions, in particular in acidic aqueous solutions, as well as in solid or semi-solid mixtures of substances.

Naloxone, {(-)12-allyl-7,7a,8,9-tetrahydro-7,3a-dihydroxy-4aH-8,9c-iminoethanophenathro[4,5-bed]furan-5,6&EEgr;-&ogr;&eegr;} is a morphine antagonist (Narcanti ) of the formula

OH

—CHyCH=CH ₂

from the group of phenanthrene alkaloids.

Until now, it has been assumed that naloxone and its salts such as the hydrochloride are fairly stable compounds.

which are not subject to any significant decomposition (oxidation, dimerization, rearrangement, etc.) even in acidic solutions and under the influence of radical formers such as oxygen.

However, recent long-term studies have shown that naloxone, contrary to the established view of experts, is a substance that, under unfavorable conditions, e.g. those that support the formation of radicals, is particularly prone to undesirable intramolecular reactions, but can also react with accompanying substances. The chemical course of these reactions has not yet been investigated in detail, so that preventing them must initially rely on empirical approaches and experiments.

It is currently assumed that dimeric naloxone derivatives, and in particular 2,2'-bisnaloxone, are formed in a selective reaction according to formula I. According to unpublished studies, this reaction is promoted by nitrogen-containing organic compounds that are also present in the solution. This dimerization is probably triggered by oxidizing substances and/or radicals, which are always present in small amounts. The spontaneous and selective formation of bisnaloxone has not yet been described in the literature and is surprising, especially in aqueous, acidic solutions, since the formation of dimeric compounds of related substance classes usually requires fairly drastic reaction conditions and an alkaline environment, or the use of strongly oxidizing enzymes.

The object of the present invention is to prevent the undesirable intramolecular conversion to bisnaloxone, but also the intermolecular reactions of naloxone with accompanying substances, and thus to effectively stabilize naloxone and its salts, in particular as an active ingredient in solid and liquid pharmaceutical forms.

To solve this problem, model reactions were first developed that lead to bisnaloxone (just like the spontaneous dimerization of naloxone). In contrast to the spontaneous dimerization that can usually be observed after a few weeks under stress conditions, these model reactions should proceed in the same way over a period of a few hours to days. In a second step, it was then investigated how the induced side reactions could be suppressed as quantitatively as possible.

Suitable model reactions have been found to be heating hydrochloric acid naloxone hydrochloride solutions to 70 ⁰ C for several hours, oxidation of the solution with a dilute potassium permanganate solution in the acidic range, oxidation with a suspension of iron(III) oxide in hydrochloric acid solution, heating the solution in the presence of azobisisobutyronitrile, and irradiating a naloxone hydrochloride solution containing azobisisobutyronitrile with intense daylight. All reactions initially led very selectively to the formation of bisnaloxone in amounts of approx. 5 - 10%, irradiation of the solution resulted in up to 40% bisnaloxone. With longer reaction duration and under

Under more drastic conditions, other conversion products of naloxone hydrochloride naturally also occurred.

As part of the extensive investigations, the inhibitory effect of a whole series of substances was tested. These substances were added to solutions containing naloxone hydrochloride in defined quantities and the resulting mixtures were subjected to one or more model reactions.

First, typical radical scavengers or antioxidants were used. The effectiveness of the inhibitors was tested based on the delayed or non-observed formation of bisnaloxone. HPLC methods and HPTLC methods specifically suited for this purpose were developed to quantify bisnaloxone in solutions containing naloxone hydrochloride.

Antioxidants 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 as Tocofersolan® or tocopherol acetate have been shown to be surprisingly effective as stabilizers even in extremely low concentrations. But sulfites, bisulfites and hydrogen sulfites of potassium, calcium and other metals also show a good dimerization-inhibiting effect.

Surprisingly, compounds whose antioxidant and radical-scavenging effects are otherwise hardly noticeable or not known at all were also effective: PHB esters, BHA, BHT, gallates and lower fatty acids such as formic, acetic and propionic acid, fruit acids such as e.g.

Malic, fumaric, lactic, citric and tartaric acid, but also phosphoric acids such as orthophosphoric acid, sorbic 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, ethylenediaminetetraacetic acid and its salts, citraconic acid, cysteine, L-cystine, conidendrines, diethyl carbonates, methylenedioxyphenols, cephalins, ß,ß"-dithiopropionic acid, biphenyl and other phenyl derivatives.

Salts of nitric and nitrous acid have a weak inhibiting effect.

By adding the specified inhibitors in the appropriate concentrations, which can be determined quickly and reliably for the respective composition using the short tests described, naloxone can be excellently and safely stabilized, especially in medicinal products that contain other excipients and active ingredients.

The subject of the utility model are solid, semi-solid or liquid pharmaceutical forms containing naloxone or a pharmacologically acceptable salt of naloxone, characterized in that the pharmaceutical forms contain a stabilizer preventing the dimerization of the naloxone in a concentration of 0.001 to 5% by weight, preferably 0.001 to 1% by weight, particularly preferably 0.01 to 0.5% by weight, based on the total mass of the substance mixture.

The feasibility is explained in more detail below using examples. However, they are not intended to limit the present invention in any way.

example 1

61.15 mg naloxone hydrochloride are dissolved in 10 ml distilled water. The solution is stored in a sealed glass vial at 40 ⁰ C. This storage temperature corresponds to the temperature prescribed in the ICH guidelines for the stability testing of medicinal products for stress stability tests. After 15 days or 2 months, the bisnaloxone content of the solution is determined by HPLC. Figure 2 shows that the bisnaloxone content has increased from <0.01% in the starting solution to 0.2% after 2 months.

Example 2

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

Example 3

61.15 mg of naloxone hydrochloride are dissolved in 10 ml of distilled water. A) 0.8 mg of iron(III) oxide is added to the solution (series 1), a solution prepared in the same way

b) 0.8 mg of azobisisobutyronitrile (AIBN) (series 2) and 0.85 mg of potassium permanganate (series 3) are added to a prepared naloxone hydrochloride solution in water. The solutions are stored in sealed glass vials. Solutions a) and c) are stored at room temperature, solution b) is also stored at room temperature, but the solution is also irradiated in a light cabinet with light similar to daylight. Figure 3 shows that considerable amounts of bisnaloxone are formed in all solutions.

Example 4

Four solutions of naloxone hydrochloride in distilled water are prepared as described in Example 1. 10.1 mg of ascorbic acid are added to solution A, 9.8 mg of sodium sulfite to solution B, 9.5 mg of sodium bisulfite to solution C and 20.6 mg of tocopherol acetate to solution D. The solutions are filled into sealed glass vials and heated to 70 ^° C for several days as described in Example 2. The formation of bisnaloxone is determined using chromatographic methods. Figure 4 shows that all of the substances mentioned have an inhibiting effect. This may be less pronounced with ascorbic acid than with the other compounds used due to the known pH and temperature instability of the substance.

This example demonstrates that the proposed substances are able to prevent the formation of bisnaloxone in acidic naloxone hydrochloride solutions.

Example 5

Four solutions of naloxone hydrochloride in distilled water are prepared as described in Example 1. Sufficient amounts of sodium bisulfite are added to each solution to produce solutions containing 0.001% by weight of bisulfite (= solution E), 0.01% by weight of bisulfite (= solution F), 0.1% by weight of bisulfite (= solution G) and 1% by weight of bisulfite (= solution H). These solutions are subjected to the model reaction described in Example 3 under c), i.e. oxidation with small amounts of potassium permanganate at room temperature. Figure 5 shows that, depending on the bisulfite concentration, a varying degree of inhibition can be detected. Bisulfite concentrations of around and below 0.01% inhibit only weakly or not at all in this model reaction, whereas concentrations above 0.01% inhibit significantly.

Example 6

Prepare four solutions of naloxone hydrochloride in distilled water as described in Example 1. Add enough sodium bisulfite to each solution to obtain solutions containing 0.001% by weight of bisulfite (= solution I), 0.01% by weight of bisulfite (= solution K), 0.1% by weight of bisulfite (= solution L) and 0.2% by weight of bisulfite (= solution M). These solutions are subjected to the mode reaction described in Example 2, ie the solutions are heated to ^70° C for several days. Figure 6 shows that an inhibiting effect is evident at all bisulfite concentrations.

which varies in intensity depending on the bisulfite concentration, but is detectable in any case.

Claims (4)

PROTECTION CLAIMS 1. Solid, semi-solid or liquid pharmaceutical form containing naloxone or a pharmacologically acceptable salt of naloxone, characterized in that the pharmaceutical form contains at least one stabilizer preventing the dimerization of the naloxone in an amount of 0.001 to 5% by weight, based on the total mass of the mixture of substances 2. Pharmaceutical form according to claim 1, characterized in that it contains at least one stabilizer in an amount of 0.01 to 1% by weight. 3. Pharmaceutical form according to claim 1 and 2, characterized in that it contains at least one stabilizer in an amount of 0.01 to 0.5% by weight. 4. Pharmaceutical form according to claims 1-3, characterized in that the stabilizer is selected from : Sulfur dioxide, sodium sulfite, sodium bisulfite, ascorbic acid and its derivatives and tocopherol and its water and fat-soluble derivatives such as Tocofersolan® or tocopherol acetate, sulfites, bisulfites and hydrogen sulfites of alkali, alkaline earth and other metals, PHB esters, BHA, BHT, gallates and lower fatty acids, fruit acids, phosphoric acids, sorbic and benzoic acid and their salts, esters, Derivatives and isomeric compounds, ascorbyl palmitate, lecithins, mono- and polyhydroxylated benzene derivatives, ethylenediaminetetraacetic acid and its salts, citraconic acid, cysteine, L-cystine, conidendrines, diethyl carbonates, methylenedioxyphenols, cephalins, S,ß"-dithiopropionic acid, biphenyl and other phenyl derivatives to prevent the dimerization of naloxone.