Stabilisation of naloxone hydrochloride

The subject of the invention is a method of stabilization in naloxone solutions, especially in acidic aqueous solutions, as well as in solid or semi-solid mixtures of substances, especially in drugs. The invention furthermore relates to pharmaceutical compositions, in particular drugs, containing a stabilizer to prevent naloxone to bisnaloxone dimerization, and the use of stabilizing agents to prevent naloxone dimerization.

Naloxone, {(-) 12-allyl-7,7a, 8,9-tetrahydro-7,3a-dihydroxy-4aH-8,9c-iminoethane phenanthro [4,5-bcd] furan-5,6H-one} is morphine antagonist (Narcanti®) of formula

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from the group of phenanthrene alkaloids.

Until now, it has been assumed that naloxone and its salts, for example the hydrochloride salt, are quite stable compounds, which also in acidic solutions and under the influence of substances forming free radicals, such as, for example, oxygen, are not subject to significant degradation (oxidation, dimerization, rearrangement, etc. .).

New, long-term studies have shown, however, that naloxone - in contrast to the views among professionals - is a substance that, under unfavorable conditions, e.g. those that promote the formation of free radicals, is in particular prone to undesirable intramolecular reactions, but can also react with substances

190 293 accompanying. The course of these chemical reactions is not yet thoroughly studied, so that their prevention must be based on experimental procedures and tests.

It is currently assumed that dimeryl naloxone derivatives, especially 2,2'-bisnaloxone, are formed in the selective reaction according to scheme 1. According to unpublished studies, this reaction is further enhanced by the nitrogen-containing organic compounds present in the solution. Dimerization is probably initiated by oxidants and / or free radicals that are always present in small amounts. The spontaneous and selective progressive formation of bisnaloxone has not been described in the literature until now and is particularly surprising in acidic aqueous solution, because the formation of dimers of this class of compounds usually requires quite drastic reaction conditions and an alkaline environment, or the use of enzymes with strong oxidizing activity.

The object of the invention is to prevent undesirable intramolecular conversion to bisnaloxone, as well as between the molecular reactions of naloxone with accompanying substances, and thus to effectively stabilize naloxone and its salts, especially as active substances in solid and liquid drugs.

To achieve this goal, model responses were first developed that (like spontaneous naloxone dimerization) lead to bisnaloxone. In contrast to spontaneously occurring dimerization, which in extreme conditions can usually be observed after a few weeks, these model reactions should occur to the same extent over several hours to several days. In a second step, it was investigated how the side reactions caused could be inhibited quantitatively.

Appropriate model reactions consisted in heating the solutions of naloxone hydrochloride in hydrochloric acid for 70 hours, oxidizing the solution with a dilute solution of potassium permanganate in an acidic environment, oxidation combined to form a suspension of iron (III) oxide in hydrochloric acid, heating the solution in the presence of azobisisobuty ronitrile, as well as irradiating naloxone hydrochloride solution containing azobisisobutyronitrile under intense daylight.

All reactions first lead very selectively to the formation of bisnaloxone in an amount of about 5 - 10%, irradiation of the solution leads to the formation of up to 40% bisnaloxone. With a longer duration of the reaction and under drastic conditions, other naloxone hydrochloride transformation products naturally also arise.

As part of extensive research, the inhibitory effects of several substances were tested. These substances were added in certain amounts to naloxone hydrochloride solutions and the obtained mixtures were subjected to one or several model reactions.

First, typical radical acceptors or antioxidants were used. The effectiveness of inhibitors was tested on the basis of delayed or unobserved formation of bisnaloxone. For the quantitative assessment of bisnaloxone content in naloxone hydrochloride solutions, HPLC and HPTLC methods especially suitable for this purpose were developed.

Antioxidants such as sulfur dioxide, sodium sulfite, sodium bisulfite, ascorbic acid and its derivatives and tocopherol, as well as its dissolution in water and fat derivatives, such as tocopherosolan® or tocopherol acetate. However, also potassium, calcium and other metal sulfites and bisulfites have a well inhibiting effect on dimerization.

Surprisingly, also effective were compounds whose antioxidant and radical scavenging activity is poorly marked or not known at all: PHB, BHA, BHT esters, gallates and lower fatty acids such as formic, acetic and propionic acids, organic acids found in fruits such as malic, fumaric, lactic, citric and tartaric acids, as well as phosphoric acids, e.g. orthophosphoric acid, sorbic acid and benzoic acid and their salts, esters, derivatives and isomers, ascorbylpalmitate, lecithin, one or multiple hydroxylated benzene derivatives, such as e.g. phenol, hydroquinone or cresol, ethylenediamine tetraacetic acid and its salts, citraconic acid, cysteine L-cystine, conidendrine, diethyl carbonate, methylenedioxyphenols, cephalins, β, β-dithiopropionic acid, biphenyl and other phenyl derivatives.

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Nitric and nitrous acid salts have poorly inhibitory properties.

Maloxone is perfectly and reliably stabilized by the addition of the mentioned inhibitors at the appropriate concentration, which can be determined quickly and without errors for each composition, using the accelerated tests described above, especially in medicines containing other excipients and active substances.

The subject of the invention is a method of stabilizing naloxone and its salts, contained in particular in liquid or solid drugs except for the transdermal therapeutic system, TTS, and the parenteral drug form containing methyl- and propylparaben, TTS, characterized in that an organic or inorganic stabilizer selected from a group including:

sulfur dioxide, sulfuric acid, sodium sulfite, sodium bisulfite, ascorbic acid and its derivatives, and tocopherol, as well as its water and fat soluble derivatives, e.g. like tocopherosolate or tocopherol acetate, sulfites and bisulfites of alkali metals, alkaline earth metals and other metals, PHB, BHA, BHT ester, gallates and lower fatty acids, organic acids found in fruits, phosphoric acids, sorbic and benzoic acids and their salts, esters , derivatives and isomers, ascorbylpalmitate, lecithin, one or more hydroxylated benzene derivatives, ethylenediammotetraacetic acid and its salts, citraconic acid, cysteine, L-cystine, conidendrin, diethyl carbonate, methylenedioxyphenols, cephalins, β, β-dithiopropionic acid, biphenyl and other phenyl derivatives, in an amount preventing dimerization of naloxone to 2,2'-dinaloxone, and from 0.001 to 5% by weight based on the total weight of the drug.

Preferably, sulfur dioxide, sulfuric acid or alkali or alkaline earth metal salts of this acid, or ethylenediammetetraacetic acid or its salts are used as the stabilizer. The stabilized drugs preferably contain other excipients and active ingredients. The stabilizer is especially used in an amount of 0.001 to 1% by weight based on the total weight of the drug, and most preferably in an amount of 0.001 to 0.5% by weight based on the total weight of the drug.

In another embodiment, the invention relates to a solid, semi-solid or liquid drug, except for the transdermal therapeutic system, TTS, and a parenteral drug formulation containing methyl- and propylparaben, containing naloxone or a pharmacologically acceptable salt of naloxone, characterized in that the drug contains at least one stabilizer selected from the group consisting of:

sulfur dioxide, sulfuric acid, sodium sulfite, sodium bisulfite, ascorbic acid and its derivatives, and tocopherol, as well as its water and fat soluble derivatives, e.g. like tocopherosolate or tocopherol acetate, sulfites and bisulfites of alkali metals, alkaline earth metals and other metals, PHB, BHA, BHT ester, gallates and lower fatty acids, organic acids found in fruits, phosphoric acids, sorbic and benzoic acids and their salts, esters , derivatives and isomers, ascorbylpalmitate, lecithin, one or multiple hydroxylated benzene derivatives, ethylenediaminetetraacetic acid and its salts, citraconic acid, cistern, L-cystine, conidendrin, diethyl carbonate, methylenedioxyphenols, cephalins, β, β-dithiopropionic acid, biphenyl and other phenyl derivatives, preventing dimerization of naloxone in an amount of 0.001 to 5% by weight, preferably in an amount of 0.001 to 1% by weight based on the total weight of the drug, and most preferably amounts from 0.001 to 0.5% by weight based on the total weight of the drug. The drug preferably contains other excipients and active substances. As a stabilizer, the drug preferably contains sulfur dioxide, sulfuric acid or alkali or alkaline earth metal salts of this acid, or ethylenediammetetraacetic acid or its salts.

Another embodiment of the invention is the use for the prevention of dimerization of naloxone at least one substance except the percutaneous therapeutic system (TTS) and the parenteral drug form containing methyl- and propylparaben, containing naloxone or a pharmacologically acceptable salt of naloxone from the group consisting of:

sulfur dioxide, sulfuric acid, sodium sulfite, sodium bisulfite, ascorbic acid and its derivatives and tocopherol, as well as its water and fat soluble derivatives, such as tocopherosolate or tocopherol acetate, sulfites and bisulfites of alkali metals, alkaline earth metals and others metals, PHB ester, BHA, BHT, gallates and lower fatty acids, organic acids found in fruits, phosphoro6 acids

190 293 EC, sorbic and benzoic acid and their salts, esters, derivatives and isomers, ascorbylpalmitate, lecithin, mono or multiple hydroxylated benzene derivatives, ethylenediaminetetraacetic acid and its salts, citraconic acid, cystine, L-cystine, conidendrin, diethoxylene carbonate cephalins, p, p-dithiopropionic acid, biphenyl and other phenyl derivatives. Preferably, sulfur dioxide, sulfuric acid or the alkali or alkaline earth metal salts of the acid or ethylenediaminetetraacetic acid or its salts are preferably used as the substance. Preferably the prevention of dimerization occurs in a liquid or solid drug.

With preferred aqueous solutions, the stabilizer, if possible, is added in a water-soluble form, e.g. in the form of a salt. In solid or semi-solid forms of the drug, the stabilizer should be thoroughly dispersed to ensure full protective effect by being tightly combined with naloxone.

The invention is explained in more detail on the basis of the following examples. In no case are these examples restrictive.

Example 1

61.15 mg naloxone hydrochloride was dissolved in 10 ml distilled water. The solution was stored in closed glass bottles at 40 ° C. This storage temperature corresponds to the temperature prescribed by the ICH directive for accelerated drug stability testing. After 15 days or 2 months, the bisnaloxone content was determined by HPLC. It can be seen in Figure 2 that the bisnaloxone content increases from &lt;0.01% in the stock solution to 0.2% after two months.

Example 2

61.15 mg naloxone hydrochloride was dissolved in 10 ml distilled water. The solution was heated in sealed glass bottles to 70 ° C and the formation of bisnaloxone was measured by HPLC for several days. It can be seen in Figure 2 that the bisnaloxone content increases to about 3% within 9 days, relative to the amount of naloxone used.

Example 3

61.15 mg naloxone hydrochloride was dissolved in 10 ml distilled water. To solution a) 0.8 mg iron (III) oxide (I series) was added. 0.8 mg azobisisobutyronitrile (AIBN) (series 2) was added to the same naloxone hydrochloride solution b), and 0.85 mg potassium permanganate (series 3) was added to another solution c).

The solutions were stored in closed glass bottles.

Solutions a) and c) were kept at room temperature, and solution b) was also kept at room temperature, additionally irradiating it in the platesetter with daylight characteristics. It can be seen from Figure 3 that significant amounts of bisnaloxone are formed in all solutions.

Example 4

As described in Example 1, four solutions of naloxone hydrochloride were prepared in distilled water. To solution A, 10.1 mg of ascorbic acid was added, to solution B, 9.8 mg of sodium sulfite, to solution C, 9.5 mg of sodium bisulfite, and to solution D, 20.6 mg of tocopherol acetate. These solutions were placed in closed glass bottles and, as in example 2, they were heated at 70 ° C. The formation of bisnaloxone was determined by chromatography. In fig. 4 it can be seen that all substances mentioned have an inhibitory effect. In the case of ascorbic acid, perhaps due to the known instability of this substance under the influence of pH and temperature, this effect is less pronounced than with other compounds used.

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

Example 5

As described in Example 1, four solutions of naloxone hydrochloride were prepared in distilled water. To each solution was added so much sodium bisulfite that the resulting solutions contained 0.001% by weight of bisulfite (solution E), 0.01% by weight of bisulfite (solution F), 0.1% by weight of bisulfite (solution G) 1% by weight of bisulfite (solution H). These solutions were subjected to the model reaction mentioned in example 3 as c), i.e. oxidation with a small amount of potassium permanate at room temperature. It can be seen in Fig. 5 that depending on the bisulfite concentration a variation in the inhibitory effect developed is observed. Bisulphite concentrations below 0.01% inhibit the model reaction only weakly or not at all, while above 0.01% this effect is clear.

Example 6

As described in Example 1, four solutions of naloxone hydrochloride were prepared in distilled water. To each solution was added so much sodium bisulfite that the resulting solutions contained 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 were subjected to the model reaction described in Example 2, i.e. heating the solutions for several days at 70 ° C. It can be seen in Fig. 6 that at all bisulfite concentrations an inhibitory effect is observed, the variation developed depending on the bisulfite concentration.

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Diagram 1

Formation of 2,2'-bisnaloxone from naloxone in acidic aqueous solutions

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2,2'-bisnalokson

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Fig. 2

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Blanaloksonu

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Fig 2a

Formation of 2.2-blanaloxone from naloxone hydrochloride in acidic formulations

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% Blanaloxone

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Fig 3

Reaction with ielase (III) oxide (rotor a) Reaction with A1BN and light (rotor b)

Reaction with potassium permanganate (Form c)

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Fig 4 [ownership];

Naloxone hydrochloride reference solution in water Ascorbic acid as inhibitor (Rotor A)

Sodium sulfite as an inhibitor (Works B)

Sodium bisulphite as an inhibitor (solution C)

Inhibiting effect of the substance &lt;o

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% Blanaloxone

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Fig 5

Calcium derivative equation in food water in 0.001% sodium seaweed (E-grade) 0.01% sodium hydrogen sulphate (Formula F)

XI

Inhibitory effect of sodium hydrogen hydrogel under oxidative conditions

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% Bisnaiokaon

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Inhibiting the effect of sodium bisulfite at 70 ° C

Fig. 6 o— Comparative preparation of naloxone hydrochloride in water -O— 0.001% sodium bisulfite etherification (solution I)

B 0.01% sodium bisulfite stent (K solution)

B 0.1% sodium bisulphite (solution L) ® 0.2% equivalent to sodium bisulphite (solution H)

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% Bisnaloxone

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