SK109299A3 - Stabilization of naloxonhydrochloride - Google Patents

Abstract

Disclosed is a stabilization method of naloxone and salts th ereof by preventing dimerization of naloxone to 2,2'-dinaloxone b y means of suitable stabilizers, especially sulphur dioxide and s odium sulphite.

Description

Method for stabilizing naloxone hydrochloride

Technical field

The present invention relates to a process for stabilizing naloxone in solutions, in particular in aqueous acidic solutions, as well as in solid or semi-solid mixtures of substances, in particular in medicaments. The invention further relates to mixtures of substances, in particular dosage forms, which contain a stabilizer which prevents dimerization of naloxone to bisnaloxone.

BACKGROUND OF THE INVENTION

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

- CH _r CH-CH ₂ from the group of phenanthrene alkaloids.

Up to now, it has been assumed that naloxone and its salts, such as hydrochloride, are considerably stable compounds which, even in acidic solutions and under the action of radical-forming substances, such as oxygen, do not undergo any decomposition (oxidation, dimerization, rearrangement, etc.) worthy of mention. .

Recent long-term research, however, has shown that naloxone, in contrast to the established opinion of the professional world, is a substance which, under unfavorable conditions, such as those which promote the formation of radicals, tends to give rise to undesirable intramolecular reactions, but can also react with primes. The chemical course of these reactions has not yet been investigated more precisely, so their prevention must be based on empirical formulations and experiments.

At this time, it is believed that in the selectively progressing reaction according to Reaction Scheme I, dimeric derivatives of naloxone, in particular 2,2'-bisnaloxone, are formed. According to unpublished research, this reaction is supported by nitrogenous organic compounds additionally present in solution. This dimerization is probably caused by oxidizing agents and / or radicals, which are always available in small amounts. The spontaneous and selectively occurring formation of bisnaloxone has not been described in the literature to date and is particularly surprising in acidic aqueous solution, since the formation of dimeric compounds of related classes of substances generally requires very drastic reaction conditions and an alkaline environment or the use of strongly oxidizing enzymes.

It is already known from WO 97/33566 to add antioxidants to certain drugs, which may contain, among other substances, naloxone. However, it is not possible to understand what the antioxidants are supposed to cause, in particular nothing about the tendency of naloxone to dimerize.

New Party

It is known from DE 44 23 850 to improve the color stability of a naloxone transdermal patch by means of dimethylsulfoxide or ascorbyl palmitate. The document does not disclose the potential stabilization of naloxone by preventing its dimerization.

From Biochemical and Biophysical Research Communications Vol. 131, no. 1, 1985, pages 299 to 306, XP002067436, it is known that Narcan®, a parenteral formulation containing naloxone, contains methylparaben and propylparaben as preservatives. The document does not mention anything about potentially preventing dimerization of naloxone.

The object of the present invention is to prevent undesired intramolecular conversion to bisnaloxone, but also intermolecular reactions of naloxone with admixtures, thereby effectively stabilizing naloxone and its salts, in particular as active ingredient in solid and liquid dosage forms.

SUMMARY OF THE INVENTION

To address this challenge, model reactions have initially developed which (as well as spontaneously occurring dimerization of naloxone) lead to bisnaloxone. Contrary to the spontaneously occurring dimerization, which can usually be observed under load conditions after a few weeks, these model reactions should run in the same way over a period of several hours to days. The second step then examined how the induced side reactions could be suppressed as quantitatively as possible.

A suitable model of the reaction was shown to several hours of heating the solution naloxone hydrochloride in hydrochloric acid at 70 ^e C, the oxidation of a dilute solution of potassium permanganate in the acid range, the oxidation of iron oxide suspension in hydrochloric acid,

The altered sheet heats the solution in the presence of azobisisobutyronitrile and irradiates the naloxone hydrochloride solution containing azobisisobutyronitrile with intense daylight. All reactions initially led very selectively to formation of bisnaloxone in amounts of about 5-10%, irradiation of the solution yielded up to 40% bisnaloxone. With longer reaction times and more drastic conditions, other naloxone hydrochloride conversion products naturally also occurred.

Extensive research has investigated the inhibitory effect of a variety of substances. These were added to solutions containing naloxone hydrochloride in defined amounts, and the mixtures obtained were subjected to one or more model reactions.

At first, typical radical scavengers or antioxidants were used. The potency of the inhibitors was tested on the basis of delayed or unobserved formation of bisnaloxone. Especially suitable HPLC and HPTLC methods have been developed for the quantification of bisnaloxone in naloxone hydrochloride containing solutions.

Surprisingly, at very low concentrations, 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 proved to be effective stabilizers. However, sulfites, bisulfites and hydrogensulfites of potassium, calcium and other metals also show a good dimerization inhibiting effect.

Strangely, however, compounds whose antioxidant and radical scavenging effect are hardly possible or unknown at all: PHB-ester, BHA, BHT, gallates, as well as lower fatty acids such as formic acid, acetic acid and acid propionic, fruit acids such as malic acid, fumaric acid, lactic acid, citric acid and tartaric acid, but also phosphoric acids such as trihydrogenphosphoric acid, sorbic acid and benzoic acid, as well as their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate, lecithins, one or more times hydroxylated benzene derivatives, such as phenol, hydroquinone or cresol, ethylenediaminetetraacetic acid and its salts, citraconic acid, cysteine, L-cystine, conidendrin, diethyl carbonates, methylenedioxyphenols, dithiopinynylphenols, dithioprophines, dithaloprophines biphenyl and other phenyl derivatives. The salts of nitric acid and nitric acid have a weak inhibitory effect.

By the addition of said inhibitors, in particular sulfur dioxide, sulfuric acids or their alkali or alkaline earth metal salts or ethylenediaminetetraacetic acid or its salts in suitable concentrations, which can be quickly and reliably determined by the described short test for a given composition, naloxone can be excellent and especially in medicaments containing other excipients and active ingredients.

The present invention therefore provides a process for stabilizing naloxone and its salts, in particular in liquid or solid dosage forms, characterized in that an organic or inorganic stabilizer, in particular sulfur dioxide, sulfuric acid or its alkali or alkaline earth metal salts or acid is added. ethylenediaminetetraacetic acid or salts thereof in an amount that prevents dimerization of naloxone to bisnaloxone. Generally, an amount of 0.001 to 1% by weight, based on the total weight of the naloxone mixture, is sufficient. Particularly preferred stabilizers are sulfur dioxide, optionally sulfuric acid, and sulfuric acid

Novel side of pharmacologically compatible salts, especially alkali and alkaline earth metal salts thereof and ethylenediaminetetraacetic acid or salts thereof. In preferably aqueous solutions, the stabilizer is preferably added in a water-soluble form, for example as a salt. In solid or semi-solid dosage forms, the stabilizer should be finely dispersed to ensure that it can fully exert its protective effect in the closest possible association with naloxone.

A further object of the invention are solid, semi-solid or liquid dosage forms comprising naloxone or a pharmacologically acceptable salt of naloxone, characterized in that the dosage forms contain a stabilizer to prevent dimerization of naloxone in a concentration of 0.001 to 5% by weight, preferably 0.001 to 1% by weight, especially preferably 0.01 to 0.5% by weight, based on the total weight of the mixture of substances; The following are excluded:

(a) transdermal therapeutic systems (TTS); and

(b) parenteral preparations containing methylparaben and propylparaben.

In the following, the invention is explained in more detail by way of examples. However, these are not intended to limit the present invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

61.15 mg of naloxone hydrochloride are dissolved in 10 ml of desiccated water. Store the solution in a sealed glass vial at 40 ° C. This storage temperature corresponds to the temperature for stability load tests prescribed in the ICH guidelines for drug stability testing. After 15 days or 2 months, the bisnaloxone content of the solution is determined by HPLC. Figure 2 shows that the bisnaloxone content, which was less than 0.01% in the starting solution, increased to 0.2% after 2 months.

Example 2

61.15 mg of naloxone hydrochloride are dissolved in 10 ml of distilled water. Heat the solution in a sealed glass vial to 70 ° C and measure bisnaloxone formation by HPLC over several days. Figure 2 shows that the bisnaloxone content increased to approximately 3% over 9 days relative to the naloxone used.

Example 3

61.15 mg of naloxone hydrochloride are dissolved in 10 ml of distilled water. A) 0.8 mg of ferric oxide (row 1) is added to the solution, b) 0.8 mg of azobisisobutyronitrile (AIBN) (row 2) is added to a solution of naloxone hydrochloride in water prepared in the same manner, and 0, 8 mg of potassium permanganate (Series 3). The solutions are stored in closed glass vials. Solutions a) and c) are kept at room temperature, solution b) is also kept at room temperature, but additionally this solution is irradiated in the light box with light similar to daylight. Figure 3 shows that significant amounts of bisnaloxone are produced in all solutions.

Example 4

Four solutions of naloxone hydrochloride in distilled water are prepared as described in Example 1. To solution A add 10.1 mg of ascorbic acid, solution B 9.8 mg of sodium sulfite, solution C of 9.5 mg of sodium bisulfite and solution D 20.6 mg tocopherol acetate. The solutions are filled into sealed glass vials and heated to 70 ° C for several days as described in Example 2. Bisnaloxone formation is determined by chromatographic methods. Figure 4 shows that all of the compounds have an inhibitory effect. This may be less pronounced in the case of ascorbic acid, due to the known thermal and pH-dependent lability of the substance, than with the other compounds used. This example demonstrates that the proposed substances are capable of preventing the formation of bisnaloxone in acidic solutions of naloxone hydrochloride.

Example 5

Four solutions of naloxone hydrochloride in distilled water were prepared as described in Example 1. To the solutions was added enough sodium bisulfite to produce solutions containing 0.001 wt. % bisulfite (solution E), 0.01 wt. % bisulfite (solution F), 0.1 wt. % bisulfite (solution G) and 1 wt. bisulfite (solution H). These solutions are subjected to the model reaction set forth in Example 3 under c), i.

oxidation with a small amount of potassium permanganate at room temperature. Figure 5 shows that, depending on the bisulfite concentration, a distinctly strong inhibitory effect is detectable. Bisulfite concentrations of 0.01% and below 0.01% inhibit only weakly at all, above 0.01%, clearly in this model reaction.

Example 6

Four solutions of naloxone hydrochloride in distilled water were prepared as described in Example 1. To the solutions was added enough sodium bisulfite to produce solutions containing 0.001 wt. % bisulfite (solution I), 0.01 wt. % bisulfite (solution K), 0.1 wt. % bisulfite (solution L) and 0.2 wt. bisulfite (solution M). These solutions are subjected to the model reaction described in Example 2, i. the solutions are heated to 70 ° C for several days. Figure 6 shows that, at all bisulfite concentrations, an inhibitory effect is detectable, which is differently strong according to the bisulfite concentration but is detectable in each case.

Example 7

To demonstrate the particular effectiveness of EDTA or its salts, the comparative data published in DE-GBM 29 720 448.3 is used in this example:

1. Load test

The formulations of Example (a) were prepared according to the following point 2. with or without addition of Na-EDTA (0.001 wt%) in both a metal container and a glass container and then subjected to a load test (2 or 5 days at ° C). ). The results are shown in the following table.

Table 1

Default value Load test 2 days 60 ^e C Load test 5 days 60 ^e C No sodium-EDTA (prepared in metal container) 0,125% 2,406% 3,529% With addition of sodium EDTA (prepared in metal container) 0.156% 0.143% 0.142% No sodium-EDTA (prepared in glass container) 0.176% 2,696% not determined With the addition of sodium EDTA (prepared in a glass container) 0,102% 0,124% 0.119%

The results clearly show that the addition of Na-EDTA to the tilidine-naloxone-containing formulation prevents naloxone dimerization to 2,2'-bisnaloxone and accordingly the storage stability of such EDTA-added drug formulations is clearly improved.

2. Examples of Formulations of Preferred Pharmaceutical Compositions

tions according to DE-GBM 29 720 448.3 (A) 0.72 ml of solution contains: Tilidine HCl 0.5 H ₂ O 51,45 mg Naloxone HCl H ₂ O 4.40 mg Ethanol 96% 72.10 mg Hydrochloric acid 25% 1.96 mg Sodium EDTA (disodium salt) 0.007 mg (resp. 0.00098) % by weight) Purified water 587.21 mg 717,127 mg

(b) 1.0 ml of solution contains:

Tilidine HCl 0.5 H ₂ O Naloxone HCl H ₂ O Sodium benzoate

Hydrochloric acid 25% Sodium EDTA (disodium salt)

Purified water

71,458 mg

6,080 mg

1,20 mg

4,75 mg

0.015 mg (resp. 0.0014 wt%)

927.9865 mg

1011.476 mg

Claims (20)

PATENT TOOLS (new) A method for stabilizing naloxone and its salts, particularly in liquid or solid dosage forms, in addition to transdermal therapeutic systems (TTS), characterized in that an organic or inorganic stabilizer is added in an amount that inhibits the dimerization of naloxone to 2,2'- dinaloxon. The method according to claim 1, characterized in that at least one compound selected from the group consisting of: 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 I tocopherol acetate, sulphites, bisulphites and hydrogen sulphites of alkali metals, alkaline earth metals and other metals, PHBesters, BHA, BHT, gallates and lower fatty acids, fruit acids, phosphoric acids, sorbic acid and benzoic acid, as well as their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate, lecithins, one or more times hydroxylated benzene derivatives, ethylenediaminetetraacetic acid and its salts, citraconic acid, cysteine, L-cystine, conidendrin, diethyl carbonates, methylenedioxyphenols, diphenyls, biphenyls, biphenyls, biphenyls, biphenyls, biphenyls, biphenyls, biphenyls phenyl derivatives. Method according to claim 1 or 2, characterized in that the stabilizer used is sulfur dioxide, sulfuric acid or its alkali or alkaline earth metal salts. Process according to claim 1 or 2, characterized in that ethylenediaminetetraacetic acid or salts thereof is used as stabilizer. Method according to claims 1 to 4, characterized in that the dosage forms to be stabilized contain further excipients and active ingredients. The process according to claims 1 to 5, wherein the stabilizer is used in an amount of 0.001 to 5% by weight. based on the total weight of the dosage form. The process according to claims 1 to 6, characterized in that the stabilizer is used in an amount of 0.001 to 1% by weight. based on the total weight of the dosage form. A process according to claims 1 to 7, wherein the stabilizer is used in an amount of 0.001 to 0.5% by weight. based on the total weight of the dosage form. New claim 9. A solid, semi-solid or liquid dosage form except (a) transdermal therapeutic systems (TTS); and b) parenteral formulations comprising methylparaben and propylparaben comprising naloxone or a pharmacologically acceptable salt of naloxone, characterized in that the dosage form comprises at least one stabilizer preventing the dimerization of naxolone in an amount of 0.001 to 5% by weight. based on the total weight of the mixture of substances. Changed Ί -i <= +15 A dosage form according to claim 9, characterized in that it contains further excipients and active ingredients. Pharmaceutical form according to claim 9 or 10, characterized in that it contains at least one stabilizer in an amount of 0.001 to 1% by weight. based on the total weight of the dosage form. Pharmaceutical form according to claims 9 to 11, characterized in that it contains at least one stabilizer in an amount of 0.001 to 0.5% by weight. based on the total weight of the dosage form. A dosage form according to claims 9 to 12, characterized in that it contains as a stabilizer a compound selected from the group consisting of: sulfur dioxide, sodium sulphite, sodium bisulphite, ascorbic acid and its derivatives and tocopherol, as well as its water- and fat-soluble derivatives such as Tocofersolan® or tocopherol acetate, sulphites, bisulphites and hydrogen sulphites of alkali metals, alkaline earth metals and other metals, PHBesters , BHA, BHT, gallates as well as lower fatty acids, fruit acids, phosphoric acid, sorbic acid and benzoic acid as well as their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate, lecithins, benzylated once and more hydroxylated derivatives, ethylenediaminetetraacetic acid and salts thereof, citraconic acid, cysteine, L-cystine, conidendrin, diethyl carbonates, methylenedioxyphenols, cephalins, β, β'-dithiopropionic acid, biphenyl and other phenyl derivatives. Pharmaceutical form according to claim 13, characterized in that it contains sulfur dioxide, sulfuric acid and its alkali and alkaline earth metal salts as stabilizers. I Pharmaceutical form according to claim 13, characterized in that it contains ethylenediaminetetraacetic acid or a salt thereof as a stabilizer. Use of at least one of sulfur dioxide, sodium sulphite, sodium bisulphite, ascorbic acid and its derivatives and tocopherol, as well as its water- and fat-soluble derivatives such as Tocofersolan® or tocopherol acetate, sulphites, bisulphites and alkali hydrogen sulphites metals, alkaline earth metals and other metals, PHBesters, BHA, BHT, gallates, as well as lower fatty acids, fruit acids, phosphorus acids, sorbic acid and benzoic acid, as well as their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate , lecithins, once and several times hydroxylated benzene derivatives, ethylenediaminetetraacetic acid and its salts, citraconic acid, cysteine, L-cystine, conidendrine, diethyl carbonates, methylenedioxyphenols, cephalins, β, β'-dithiophenone diphenylisiloxionizone, diphenylenepropionone, diphenylenepropionone derivatives . Use of a substance according to claim 16 for preventing dimerization of naloxone, characterized in that the substance is sulfur dioxide or sulfuric acid or an alkali metal or alkaline earth metal salt thereof. Use of a compound according to claim 16 for preventing dimerization of naloxone, characterized in that it is ethylenediaminetetraacetic acid or a salt thereof. Use of a substance according to claims 16 to 18, characterized in that the prevention of dimerization takes place in a liquid or solid dosage form. Use according to claim 19, characterized in that the dosage form contains further excipients and active substances.