ES2837877A1 - GALENIC COMPOSITION, FOR ORAL USE, LIQUID, INCLUDING MELATONIN AND A ZINC SALT AND CORRESPONDING METHOD AND USE (Machine-translation by Google Translate, not legally binding) - Google Patents

Abstract

Galenic composition, for oral, liquid use, comprising melatonin and a zinc salt and corresponding method and use. Liquid galenic composition, for oral use, comprising between 0.4% and 0.6% by weight, with respect to the total weight of the composition, of melatonin and between 0.8% and 1.1% by weight of zinc, relative to the total weight of the composition, of a zinc salt. A method for its preparation comprises the stages of: (a) incorporation and dissolution of the zinc salt in water; (b) incorporation of glycerin in the solution obtained in (a); (c) dissolving the melatonin in ethyl alcohol; and (d) incorporation of the solution obtained in (c) into the solution obtained in (b). The composition is preferably used as a liquid oral galenic preparation for the treatment of sleep and mood disorders. (Machine-translation by Google Translate, not legally binding)

Description

DESCRIPTION

GALENIC COMPOSITION, FOR ORAL USE, LIQUID, INCLUDING

MELATONIN AND A ZINC SALT AND CORRESPONDING METHOD AND USE

Field of Invention

The present invention describes a galenic formulation in stable liquid form, of melatonin and a zinc salt, useful for the treatment of sleep and mood disorders. The invention also relates to a method for preparing the composition according to the invention and a use thereof.

State of the art

Sleep disorders may not be a serious pathology in itself, but they have serious implications in daily life: physical exhaustion, poor performance, daytime sleep, difficulty in meeting professional, family or social obligations.

These disorders, which appear in the form of poorly restorative sleep or disorders in the rhythm and amount of sleep or as an inverted dream or daytime sleep, are named based on their manifestations as: insomnia, hypersomnia, narcolepsy, snoring and sleep apneas, parasomnias and other disorders, restless leg syndrome, night terrors, nightmares and sleepwalking, etc.

Its origin is very varied, the consideration of cause or symptom being confusing. Sometimes, they appear as an effect of other diseases and in others, they constitute risk factors that favor the appearance of pathologies.

Also, in relation to sleep disorders, the so-called circadian rhythm sleep disorders are known. Circadian rhythms are intrinsic biological rhythms of a periodic nature that manifest themselves with an interval of 24 hours. In mammals, the most important circadian rhythm is the wake-sleep cycle, which is regulated by external signals from the environment, at which the most powerful is exposure to light-dark. Light is perceived by the retina, modulates the synthesis of melatonin («hormone of darkness») and helps to synchronize the internal clock and the natural day-night alternation, so that artificial light and the moment of its exposure can modify the production pattern of the neurohormone melatonin and affect sleep, which has been correlated with plasma levels of this.

Major clinical disorders related to circadian rhythm or plasma melatonin levels include: delay sleep phase syndrome, early sleep phase syndrome, irregular sleep-wake rhythm disorder, sleep cycle disorder -vigil other than 24 hours, syndrome of rapid change of time zone (jet-lag) and sleep disorder in the night worker.

The presence of melatonin in the regulation of the circadian rhythm has led to the therapeutic treatment of these sleep disorders with exogenous melatonin; levels typically rise at the onset of darkness, peaking in the middle of the night, between 11 p.m. and 3 a.m. Currently, pharmaceutical compositions are administered at usual doses between 2 mg and 5 mg, in the form of tablets, capsules, liquids, etc.

On the other hand, melatonin, in addition to regulating the circadian cycle, participates in a wide variety of pathophysiological processes, among which is the regulation of the immune system and the endogenous antioxidant system.

Also, it is a proven fact that melatonin levels decrease with age and that this deficiency is associated with insomnia, depression, anxiety and stress.

Likewise, recent research has linked low melatonin levels to aging and the development of neurodegenerative diseases (Bubenik et al., J. Physiol. Pharmacol. 2011, 62, 13-19). For example, document US 2006/0257502 discloses a combination (more than ten) of mitochondrial nutrients with antioxidant character, including melatonin at doses of 0.1 to 3 mg, to prevent and improve disorders related to stress and oxidative damage, such as depression, syndrome chronic fatigue, sleep disorders, immune system dysfunctions, neurodegenerative diseases, etc.

Other studies have shown that melatonin has various functions and effects on stress and related disorders (Treatment of depression, anxiety, and sleep disorders (Cauffield et al. Prim Care Pract. May 1999, 3 (3): 290-304 For their part, Acuna-Castroviejo, et al. Describe the treatment of fibromyalgia with a dose of 3 mg of melatonin (Journal of Pineal Research 2006, 40 (1), 989-9).

Common factors have also been described, such as sleep disorders in depression, anxiety, fibromyalgia and chronic fatigue, as well as a relationship between these different pathologies, oxidative stress and the immune system (Hidalgo, Rev. Soc. Esp. Pain, 2012, vol.19 no.2; Revuelta et al. Rev. Soc. Esp. Pain 2010, vol.17 no.7; http://www.institutferran.org/fatiga_cronica.htm, 2017).

On the other hand, also related to this type of pathologies, the intervention of zinc has been demonstrated (Mlyniec et al. Journal of Affective Disorders 2015, 174, 89-100; Maywald et al. Journal of Trace Elements in Medicine and Biology 29 ( 2015) 24-30; Maares et al. Archives de Biochemistry and Biophysics 2016, 1-8; Nowak et al. Pharmacological Reports 2015, 67, 659-662).

Along these lines, patent US 2009/0017136 discloses the treatment of fibromyalgia and depression with doses of 200 mg of 5-Hydroxytryptophan (a melatonin precursor) and methionine-zinc at doses of 30 mg; US 2008/0107754 describes a composition for improving sleep that contains, among other components, melatonin between 0.3 and 0.6 mg and zinc between 1 and 5 mg; US 2015/0071993 presents a composition, also to induce and improve sleep, which contains, among other components (plant extracts, vitamins and magnesium) and melatonin and zinc at doses of 3.0 mg and 25 mg, respectively.

Melatonin has been formulated in different types of pharmaceutical and dietary compositions, mainly for oral administration as tablets for direct ingestion, buccal, sublingual and in some cases for nasal administration in the form of aerosols and both for immediate release as well as delayed release or combinations of both. The last two, in order to achieve a profile similar to the melatonin concentrations that occur in the circadian rhythm.

However, the oral bioavailability of melatonin in the different types of release is low and presents great variability (Benés et al. J. Pharmaceutical Sci. 1997, 86 (10): 1115-1119), probably related, in addition to the intervariability in patients, with the low absolute bioavailability of approximately 15%, as well as the fact that melatonin is slightly soluble (approximately 0.15%). Both factors are closely related, since the amount of melatonin available prior to its absorption (bioavailability) depends on its solubility.

Gooneratne et. to the. (J. Pineal Res., 2012; 52 (4): 437-445) report that different formulations of oral melatonin have been developed, including immediate release, controlled release (sustained) and combined release (“surge-sustained release”). ) and a large number of doses have been used in clinical trials with great debate regarding the role of low doses (0.1-0.5 mg) and high doses (2-10 mg) of melatonin, presenting a highly variable bioavailability, from 1% to 74%.

Stable liquid formulations with a melatonin concentration of up to 0.1% using dextrins for solubilization are described in US 2016/0166543, sometimes combined with low concentrations of glycerin, as a sleep aid.

Also in document WO 2016/058985 a liquid composition for injections of melatonin is described, initially free of water, based on the solubility in alcohol and polyethoxylated derivatives to achieve concentrations of up to 10% of melatonin; later this solution is diluted in aqueous solution for injection.

Typical doses marketed in oral formulations are usually 2 mg to 5 mg, which are administered in a single dose, both in immediate release and in controlled release.

In the same work mentioned by Gooneratne et. al, a double-blind pharmacokinetic study is presented in adults with different oral formulations of combined release ("surgesustained release") from low dose (0.4 mg) to high dose (4.0 mg) of melatonin. It is concluded that the study suggests that the half-life, Tmax (i.e. the time at which maximum concentration (Cmax) is reached in plasma), total clearance and apparent volume of distribution are similar for low and high doses and that It is consistent with a linear pharmaceutical behavior, in the low concentration range 405+ 93 pg / ml (approx.

4,000 pg / ml for high doses), value substantially higher than the physiological melatonin level (around 40 pg / ml), which leads them to suggest that the use of high doses of melatonin results in a markedly much higher exposure higher than physiological levels, with the risk of overexposure that may persist for the rest of the day.

The interest in a therapeutic composition that combines the joint action of melatonin and zinc is disclosed in patent ES 2 684 414 (Laboratorios Viñas, SA), in which a solid oral formulation is presented in the form of tablets or capsules. containing between 0.7% and 1.2% of melatonin and between 7.0% and 12.0% of zinc (in the form of zinc salt, preferably zinc sulfate) to be able to administer doses of 1 , 0 mg of melatonin and 10.0 mg of zinc. It is demonstrated how the use of micronized melatonin allows a total bioavailability in less than 30 minutes, even at 10 minutes, of melatonin and zinc salt. However, this solid oral formulation does not provide advantages when it comes to administering melatonin and zinc to populations that manifest swallowing difficulties, such as in the geriatric population, patients with certain diseases or in children, particularly in the pediatric population, either due to It is a solid oral form, due to the limitation of the dosage or due to the organoleptic characteristics, especially due to the astringency, roughness, bitterness and acrid taste of zinc salts.

Therefore, the interest and the need to develop technical solutions that provide oral compositions, particularly in the joint formulation of melatonin and zinc, that provide pharmacotechnical qualities that are characterized by a high, homogeneous and reproducible bioavailability of the active principles, for the possibility of variable dosage, for an intake without difficulties in swallowing and with characteristics Organoleptic properties that do not make it rejectionable and that maintain stability and therapeutic qualities.

Invention Exhibition

The object of the present invention is a galenic composition, for oral use, characterized in that it is formulated as a liquid solution, comprises melatonin and a zinc salt, has tolerable organoleptic characteristics and allows a variable dosage suitable for the treatment of alterations of the sleep and moods.

Preferably the composition is in stable liquid form.

The combination of melatonin and zinc has the advantage of being able to provide a synergistic effect, given the manifestation of sleep disorders in different types of pathologies: mood, depression, anxiety, stress, chronic fatigue and fibromyalgia, and the incidence of both active ingredients. in the triggering processes of these pathologies.

In relation to the issues and complexities set out above, the inventors of this patent application have discovered that it is possible to obtain formulations of melatonin at low concentration and a zinc salt in stable, immediate-release, reproducible and homogeneous liquid form, with 100% bioavailability, both of melatonin and zinc, at the time of administration, since both active ingredients are administered dissolved.

Melatonin has a solubility of less than 0.2% in water, so it requires the use of cosolvents when higher concentrations are to be obtained.

Zinc salts are particularly known for their very astringent, harsh, bitter and pungent taste, especially zinc sulfate (Oral Zinc Sulfate Solutions Inhibit Sweet Taste Perception; Chem. Senses 29: 513-521, 2004). In general, they are quite soluble in water, which is why, normally, they do not present solubilization problems in any galenic form that has water as the main vehicle, remaining in total dissolution as a step prior to absorption. However, in the presence of organic solvents or cosolvents, such as when it is intended to mask their taste, or in combination with other water-insoluble actives, they do present difficulties. For example, zinc sulfate is insoluble in alcohol or poorly soluble in glycols.

The combination of melatonin and zinc salts and, in particular, the combination of melatonin and zinc sulfate is complex as problems of solubilization of the active ingredients and problems of masking the taste of zinc sulfate are combined. Thus, it should be taken into account that:

- melatonin is slightly soluble in water (<0.2%), but it is soluble in ethyl alcohol (2%);

- zinc sulfate monohydrate is fairly soluble in water (35%), slightly soluble in ethyl alcohol (<0.5%) and poorly soluble in glycerin (<2%); Y

- zinc sulfate, at concentrations greater than 0.1% by weight, with respect to the total weight of the composition, has a high inhibitory power of the sweet taste of various sweeteners, which requires the use of high concentrations of these.

However, after experimentation with different solvent and cosolvent vehicles, it has been observed that the combination of water, ethyl alcohol (as cosolvent) and glycerin (as cosolvent and flavor masking), despite the different solubility characteristics of the active ingredients and the high inhibitory power of the sweet taste by zinc sulfate, allows to formulate stable and organoleptically very tolerable liquid solutions. In particular, certain molar and percentage ratios between actives, solvents and cosolvents give particularly advantageous results. Thus, preferably:

- the percentage of water is between 30% and 45% by weight, with respect to the total weight of the composition (hereinafter abbreviated as "(w / w)"), preferably between 35% and 40% (p / p).

- the percentage of ethyl alcohol is between 5% and 10% (w / w), preferably between 7% and 9% (w / w).

- the molar ratio between ethyl alcohol and melatonin is between 85/1 and 115/1, preferably between 95/1 and 105/1.

- the percentage of glycerin is less than 55% (w / w), preferably between 45% and 50% (w / w).

- the percentage of glycerin is higher between 5% and 10% (w / w) than the percentage of water.

- the molar ratio between glycerin and zinc sulfate monohydrate is between 35/1 and 45/1, preferably between 38/1 and 42/1.

Likewise, the present invention proposes an advantageous liquid formulation at 0.5% (5 mg / ml) in melatonin and 1% in zinc (10 mg / ml) that allows dosing by dropper from 0.25 mg / drop of melatonin and / or 0.5 mg / drop of zinc up to the usual doses (2-5 mg) of melatonin and up to 10 mg of zinc in intake volumes of 1 ml (20 drops) and, therefore, easy to dose and with characteristics tolerable organoleptic, appropriate and desirable for pediatric and geriatric population or patients with difficulties in swallowing solids.

The present invention also relates to the process for obtaining the formulation object of the patent. The state, order of addition and proportion of the components have been developed to allow a stable and organoleptically tolerable formulation in liquid form.

Another object of the invention is the use of a pharmaceutical composition according to the invention for the treatment of sleep and mood disorders.

Brief description of the drawings

Other advantages and characteristics of the invention can be seen from the following description, in which, without any limitation, preferred embodiments of the invention are related, with reference to the accompanying drawings. Figures show: Fig. 1, effect of GV-340 treatment on sleep metrics: (A) sleep duration (hours: minutes), (B) conciliation time (minutes) and (C) evolution of the number of nocturnal awakenings. Total 38 cases. * p <0.001 between baseline and end.

Fig. 2, effect of treatment with GV-340 on the level of fatigue (A) and mood (B), before and after the end of the 5 weeks of treatment. Total 38 cases. * p <0.001 between baseline and end.

Fig. 3, global judgments on the efficacy and tolerability of GV-340 treatment. (N = 37)

Detailed description of some embodiments of the invention

A preferred embodiment of the invention consists of a galenic composition in stable liquid form, for oral use, of melatonin and a zinc salt, in a diluting and masking base for the astringency, roughness, bitterness and acrimony of the salt of zinc.

The composition is for the treatment of sleep disturbances and moods.

The composition may be in the form of a liquid solution administrable with a syringe or dropper.

The active agents in the formulation are melatonin and a zinc salt.

Melatonin can be present at a concentration, advantageously between 0.4% and 0.6% by weight relative to the total weight of the composition, preferably at 0.5%.

As the zinc salt, zinc salts of mineral organic acids can be preferably used, most preferably, most preferably zinc sulfate monohydrate.

Preferably the composition can comprise between 0.8% and 1.1% by weight of zinc relative to the total weight of the composition, of a zinc salt, preferably between 0.85% and 0.95%.

As vehicle of the formulation, a mixture of water, ethyl alcohol and glycerin is preferred at certain percentage and molar ratios between active ingredients, solvents and cosolvents:

- the percentage of water is advantageously kept between 30% and 45% (w / w), preferably between 35% and 40% (w / w).

- the percentage of ethyl alcohol as cosolvent is preferably between 5% and 10% (w / w), and most preferably between 7% and 9% (w / w).

- the molar ratio between ethyl alcohol and melatonin is preferably between 85/1 and 115/1, and most preferably between 95/1 and 105/1.

- the percentage of glycerin is advantageously less than 55% (w / w), and is preferably between 45% and 50% (w / w);

- Advantageously, the percentage of glycerin is greater between 5% and 10% (w / w) than the percentage of water.

- preferably the molar ratio between glycerin and zinc sulfate monohydrate will be between 35/1 and 45/1, and most preferably between 38/1 and 42/1.

Advantageously the pH of the solution is between pH 4.0 and pH 7.0, preferably between pH 5.0 and pH 6.0.

As pH adjusting and stabilizing agents, salts of organic acids such as sodium citrate, sodium tartrate, sodium acetate or potassium sorbate can be used.

The formulation may contain other complementary additives such as sweeteners, flavorings and flavorings in amounts less than 1%.

The invention also refers to the manufacturing process of the described composition in liquid form.

The manufacturing process is characterized by the incorporation and sequential dilution in water as a diluent base for the zinc salt; the incorporation of glycerin as a cosolvent and masking agent; the incorporation of the melatonin dissolved in ethyl alcohol and the final incorporation of the pH stabilizer dissolved in water.

The incorporation of the glycerin must be carried out at a stirring speed between 1,000 rpm and 2,000 rpm and at an addition speed such that the minimum time for the total incorporation of the glycerin is 15 min and the maximum time 45 min.

An advantageous formulation, obtained under the conditions described and with the selected components, is a composition in liquid form with a concentration of 0.5% (5 mg / ml) in melatonin and 1% in zinc (10 mg / ml) that allows to dose by dropper from 0.25 mg / drop of melatonin and 0.5 mg / drop of zinc up to the usual doses (2-5 mg) of melatonin and up to 10 mg of zinc in intake volumes of 1 ml (20 drops ) and, therefore, easy to dose and with tolerable organoleptic characteristics, appropriate and desirable for pediatric and geriatric populations or patients with difficulties in swallowing solids.

The composition may be presented in the form of a liquid dosable solution that can be administered with a syringe or dropper.

Another object of the invention is the use of a composition according to the invention as an oral liquid galenic preparation for the treatment of sleep and mood disorders.

Examples

Example 1: Formula 1

In a reactor with a suitable volume for the final total volume, 800 g of water are added and 54.5 g of zinc sulfate monohydrate are added with stirring. Stirring is maintained until the zinc salt is completely dissolved.

Incorporate, keeping stirring at 1,500 rpm, 1,070 g of glycerin for 30 min.

Dissolve 10 g of melatonin in 175 g of ethyl alcohol in a separate kit and add this solution to the previous solution.

Dissolve 4.0 g of potassium sorbate in 100 g of water in a separate kit and add this solution to the previous solution.

Keep the final solution stirring for 30 min.

Stability

1. Objective

Chemical analysis is carried out on the samples corresponding to 18 months of stability preserved at 25 ° C / 60% RH and at 30 ° C / 65% RH of the product prepared according to Formula 1 kept in a primary container: glass dropper.

2. Characteristics studied and analysis methods

The following determinations have been made by the Analytical Development department.

pH

Colour

Taste and smell

Melatonin (% m / V)

Potassium sorbate (% m / V)

Melatonin SSRR (5-Methoxytryptamine and N-Acetyl 5-hydroxytryptamine).

(*): the Zn content is not determined at this point of stability since it is not a parameter susceptible to change over time, it is not an indicative parameter of stability.

3. Results

The following tables present the results obtained:

□ pH:

□ Color:

□ Taste and smell:

□ Zn2 + (% m / V):

The Zn content is not determined after 6 months since it is not a parameter susceptible to change over time, it is not an indicative parameter of stability.

□ Melatonin (% m / V):

□ Potassium sorbate (% m / V):

□ Related substances of melatonin (% with respect to melatonin):

During the stability study it is observed that:

□ pH: it is maintained in the two conditions of conservation.

□ Color: the product does not change significantly in color over time under either of the two storage conditions studied.

□ Taste and odor: the product does not change significantly in odor or taste over time under either of the two conditions studied: acceptable and tolerable taste and odor.

□ Melatonin: concentration remains within acceptance limits and has not changed over time or storage conditions.

□ Potassium sorbate: the concentration remains within the acceptance limits and has not varied with time or storage conditions.

□ SSRR of melatonin: in the samples corresponding to the 18 months of stability, no related substances are detected above the acceptance limits.

4. Conclusion

Formula 1 samples are stable for 18 months stored at 25 ° C / 60% RH and at 30 ° C / 65% RH.

Clinical study

"Study of Organoleptic Acceptability, Tolerability and Efficacy of the Preparation GV-340 ^) in Insomnia with Decay" (2018-2019).

Department of Clinical Research. Laboratorios Viñas, S.A.

(*) GV-340 refer to Formula 1 described in this document.

Objective: To assess the organoleptic acceptability, tolerability and efficacy of the GV-340 drop solution in patients with insomnia and associated decay.

Methodology: Selection of volunteers according to medical criteria. The inclusion criteria were being of legal age and presenting insomnia with decline. Exclusion criteria were concomitant use of similar products or benzodiazepines, regular users of melatonin, or pregnancy / lactation. The expected duration of study treatment was 4 to 5 weeks. A daily intake of 8 drops (2 mg of melatonin and 4 mg of zinc) was proposed, about 30 min before going to bed.

Results: 13 investigators participated, including 38 cases with insomnia with associated decline. The distribution by sex was 27 women and 11 men with an age mean of 56 ± 17 years. The most common profiles were conciliation insomnia, maintenance insomnia, or a combination of both. On average, each case was administered 8.1 ± 0.4 drops / day, for 4.9 ± 2.2 weeks. At the end of the study with the GV-340, the quality of sleep improved in 76% of the 38 cases. Sleep duration increased by 46 minutes, on average, each night (Figure 1A). The conciliation time was reduced 2 times (Figure 1B), the nocturnal awakenings remitted in 42% of the cases, and they were reduced by 30% in those that still presented at the end of the study (Figure 1C).

The GV-340 treatment based on melatonin and zinc drops, improves sleep metrics by reducing the conciliation time and the number of awakenings, increasing the rest time, through a restful sleep that, together with the role of zinc present in the formula, it contributes to an improvement in the patient's mood (Figure 2). These results are accompanied by an excellent acceptability, tolerability, and safety profile. 89% of the patients thought that they would continue with the treatment.

Table 1. Organoleptic acceptability of GV-340

Average Dev. Its T.

Flavor 7.8 2.1

Odor 7.9 2.1

Ease of administration

8.7 1.2

(count drops)

Claims (1)

1 - Galenic composition, for oral use, in liquid form, characterized in that it comprises between 0.4% and 0.6% by weight, with respect to the total weight of the composition, of melatonin and between 0.8% and 1, 1% by weight of zinc, relative to the total weight of the composition, of a zinc salt. 2 - Composition according to claim 1, characterized in that it comprises between 0.43% and 0.5% by weight, with respect to the total weight of the composition, of melatonin. 3 - Composition according to one of claims 1 or 2, characterized in that it comprises between 0.85% and 0.95% by weight of zinc, relative to the total weight of the composition, of a zinc salt. 4 - Composition according to any of claims 1 to 3, characterized in that the zinc salt is a salt of organic acids or a mineral salt. 5 - Composition according to claim 4, characterized in that the zinc salt is zinc sulfate monohydrate. 6 - Composition according to any of claims 1 to 5, characterized in that the composition comprises a diluent base formed by a mixture of water, ethyl alcohol and glycerin. 7 - Composition according to claim 6 characterized in that it comprises a percentage of water between 30% and 45% by weight, with respect to the total weight of the composition, preferably between 35% and 40% by weight, with respect to the total weight of the composition. 8 - Composition according to one of claims 6 or 7, characterized in that it comprises a percentage of ethyl alcohol between 5% and 10% by weight, with respect to the total weight of the composition, preferably between 7% and 9% by weight , with respect to the total weight of the composition. 9 - Composition according to any of claims 6 to 8, characterized in that the molar ratio between ethyl alcohol and melatonin is between 85/1 and 115/1, preferably between 95/1 and 105/1. 10 - Composition according to any of claims 6 to 9, characterized in that it comprises a percentage of glycerin of less than 55% by weight, with respect to the total weight of the composition, preferably it comprises a percentage of glycerin between 45% and 50% by weight , with respect to the total weight of the composition. 11 - Composition according to any of claims 6 to 10, characterized in that the percentage of glycerin is greater between 5% and 10% by weight, with respect to the total weight of the composition, than the percentage of water. 12 - Composition according to any of claims 6 to 11, characterized in that the molar ratio between glycerin and zinc sulfate monohydrate is between 35/1 and 45/1, preferably between 38/1 and 42/1. 13 - Composition according to any of claims 1 to 12, characterized in that the pH of the solution is between 4.0 and 7.0, preferably between 5.0 and 6.0. 14 - Composition according to any of claims 1 to 13, characterized in that it comprises an organic acid salt as a pH adjusting and stabilizing agent, preferably from the group consisting of sodium citrate, sodium tartrate, sodium acetate and potassium sorbate. 15 - Composition according to any of claims 1 to 14, characterized in that the composition is presented in the form of a liquid solution that can be dosed and administered with a syringe or dropper. 16 - Composition according to any of claims 1 to 15, characterized in that it is packaged in a bottle with a dropper suitable for dosing an amount of 0.25 mg / drop of melatonin. 17 - Composition according to any of claims 1 to 15, characterized in that it is packaged in a bottle with a dropper suitable for dosing an amount of 0.25 mg / drop of melatonin and 0.5 mg / drop of zinc. 18 - Method for preparing a liquid oral galenic composition according to any of claims 1 to 17, characterized in that it comprises the steps of: [a] incorporation and dissolution of the zinc salt in water; [b] incorporation of glycerin in the solution obtained in step [a]; [c] dissolution of melatonin in ethyl alcohol; and [d] incorporation of the solution obtained in step [c] in the solution obtained in step [b]. 19 - Method according to claim 18, characterized in that the step [b] of incorporation of the glycerin in the solution obtained in step [a] lasts between 15 and 45 minutes. 20 - Method according to one of claims 18 or 19, characterized in that it additionally comprises the following steps: [e] dissolving the pH stabilizer in water; and [f] incorporation of the solution obtained in step [e] in the solution obtained in step [d]. 21 - Use of a galenic composition according to any of claims 1 to 17 as a liquid oral galenic preparation for the treatment of sleep and mood disorders.