WO2021136862A1 - Liquid galenic composition for oral use comprising melatonin and a zinc salt, and corresponding method and use - Google Patents

Liquid galenic composition for oral use comprising melatonin and a zinc salt, and corresponding method and use Download PDF

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Publication number
WO2021136862A1
WO2021136862A1 PCT/ES2020/070832 ES2020070832W WO2021136862A1 WO 2021136862 A1 WO2021136862 A1 WO 2021136862A1 ES 2020070832 W ES2020070832 W ES 2020070832W WO 2021136862 A1 WO2021136862 A1 WO 2021136862A1
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composition
melatonin
composition according
weight
zinc
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PCT/ES2020/070832
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Spanish (es)
French (fr)
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Antonio BUXADÉ VIÑAS
Miguel Cánovas Ubera
Antonio Conchillo Teruel
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Laboratorios Viñas S.A.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • 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.
  • 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.
  • insomnia hypersomnia, narcolepsy, snoring and sleep apneas, parasomnias and other disorders, restless leg syndrome, night terrors, nightmares and sleepwalking, etc.
  • 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.
  • melatonin «hormone of darkness»
  • 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.
  • compositions are administered at usual doses between 2 mg and 5 mg, in the form of tablets, capsules, liquids, etc.
  • 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.
  • 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).
  • 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.
  • 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.
  • the 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.
  • a double-blind pharmacokinetic study is presented in adults with different oral formulations of combined release ("surge-sustained release") from low dose (0.4 mg) to high dose (4.0 mg) of melatonin. concludes that the study suggests that the half-life, Tmax (that is, 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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 is present at a concentration between 0.4% and 0.6% by weight, relative to the total weight of the composition, preferably between 0.43% and 0.5% by weight, relative to the total weight of the composition. , and most preferably 0.5% by weight, relative to the total weight of the composition.
  • zinc salts of mineral organic acids can be preferably used, most preferably, most preferably zinc sulfate monohydrate.
  • 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%.
  • 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);
  • the percentage of glycerin is greater between 5% and 10% (w / w) than the percentage of water.
  • 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.
  • the pH of the solution is between pH 4.0 and pH 7.0, preferably between pH 5.0 and pH 6.0.
  • 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 dosing by dropper from 0.25 mg / drop of melatonin and 0.5 mg / drop of zinc 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.
  • 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.
  • 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.
  • Formula 1 samples are stable for 18 months stored at 25 ° C / 60% RH and at 30 ° C / 65% RH.
  • 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.
  • 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 believed that they would continue with the treatment.

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Abstract

The invention relates to a liquid galenic composition for oral use comprising melatonin and a zinc salt, and to the corresponding method and use. The liquid galenic composition for oral use comprises 0.4-0.6% by weight of melatonin with respect to the total weight of the composition and 0.8-1.1% by weight of zinc of a zinc salt with respect to the total weight of the composition. The invention also relates to a method for preparing same, which comprises the steps of: [a] adding the zinc salt to water and dissolving same; [b] adding glycerin to the solution obtained in step [a]; [c] dissolving melatonin in ethyl alcohol; and [d] adding the solution obtained in step [c] to the solution obtained in step [b]. The composition is preferably used as a liquid galenic oral preparation for the treatment of sleep and mood disorders.

Description

COMPOSICIÓN GALÉNICA, PARA USO ORAL, LÍQUIDA, QUE COMPRENDE MELATONINA Y UNA SAL DE ZINC Y MÉTODO Y USO CORRESPONDIENTES GALENIC COMPOSITION, FOR ORAL USE, LIQUID, INCLUDING MELATONIN AND A ZINC SALT AND CORRESPONDING METHOD AND USE
DESCRIPCIÓN DESCRIPTION
Campo de la Invención Field of Invention
La presente invención describe una formulación galénica en forma líquida estable, de melatonina y una sal de zinc, útil para el tratamiento de las alteraciones del sueño y de los estados de ánimo. La invención también se refiere a un método para preparar la composición de acuerdo con la invención y un uso de la misma. 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.
Estado de la técnica State of the art
Los trastornos del sueño pueden no ser una patología grave en sí misma, pero tienen serias implicaciones en la vida diaria: agotamiento físico, bajo rendimiento, sueño diurno, dificultad para cumplir con las obligaciones profesionales, familiares o sociales. 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.
Estos trastornos, que se presentan en la forma de un sueño poco reparador o de trastornos en el ritmo y en la cantidad de sueño o como un sueño invertido o sueño diurno, son denominados en función de sus manifestaciones como: insomnio, hipersomnia, narcolepsia, ronquido y apneas del sueño, parasomnias y otros trastornos, síndrome de las piernas inquietas, terrores nocturnos, pesadillas y sonambulismo, etc. 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.
Su origen es muy variado, siendo confusa la consideración de causa o de síntoma. En ocasiones, aparecen como efecto de otras enfermedades y en otras, constituyen factores de riesgo que favorecen la aparición de patologías. 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.
También, en relación con los desórdenes del sueño se conocen los denominados trastornos del ritmo circadiano del sueño. Los ritmos circadianos son ritmos biológicos intrínsecos de carácter periódico que se manifiestan con un intervalo de 24 horas. En mamíferos, el ritmo circadiano más importante es el ciclo vigilia-sueño, que es regulado por señales externas del entorno, a los cuales el más potente es la exposición a la luz-oscuridad. La luz es percibida por la retina, modula la síntesis de melatonina («hormona de la oscuridad») y ayuda a sincronizar el reloj interno y la alternancia natural día-noche, por lo que la luz artificial y el momento de su exposición pueden modificar el patrón de producción de la neurohormona melatonina y afectar al sueño, lo que ha sido correlacionado con los niveles plasmáticos de esta. 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.
Los trastornos clínicos principales relacionados con el ritmo circadiano o con los niveles plasmáticos de melatonina, incluyen: síndrome del retraso de la fase del sueño, síndrome del adelanto de la fase del sueño, trastorno por ritmo de sueño-vigilia irregular, trastorno por ciclo sueño-vigilia diferente de 24 horas, síndrome del cambio rápido de zona horaria (jet-lag) y trastorno del sueño en el trabajador nocturno. 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.
La presencia de melatonina en la regulación del ritmo circadiano ha llevado al tratamiento terapéutico de estos desórdenes del sueño con melatonina exógena; los niveles típicamente se incrementan al inicio de la oscuridad, llegándose a un máximo a media noche, entre las 23 y las 3 de la madrugada. Actualmente, las composiciones farmacéuticas son administradas a dosis usuales entre 2 mg y 5 mg, en forma de comprimidos, cápsulas, líquidos, etc. 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.
Por otra parte, la melatonina, además de la regulación del ciclo circadiano, participa en una gran variedad de procesos fisiopatológicos, entre los que se encuentra la regulación del sistema inmunitario y del sistema antioxidante endógeno. 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.
También, es un hecho contrastado que los niveles de melatonina disminuyen con la edad y que esta deficiencia está asociada con insomnio, depresión, ansiedad y estrés. Also, it is a proven fact that melatonin levels decrease with age and that this deficiency is associated with insomnia, depression, anxiety and stress.
Asimismo, investigaciones recientes han relacionado los bajos niveles de melatonina con el envejecimiento y con el desarrollo de enfermedades neurodegenerativas (Bubenik et al., J. Physiol. Pharmacol. 2011, 62, 13- 19). Por ejemplo, en el documento US 2006/0257502 se da a conocer una combinación (más de diez) de nutrientes mitocondriales con carácter anti oxidante, entre ellos la melatonina a dosis de 0,1 a 3 mg, para prevenir y mejorar los desórdenes relacionados con el estrés y el daño oxidativo, como la depresión, el síndrome de fatiga crónica, desordenes del sueño, disfunciones del sistema inmune, enfermedades neurodegenerativas, etc. 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 related disorders with stress and oxidative damage, such as depression, syndrome chronic fatigue, sleep disorders, immune system dysfunctions, neurodegenerative diseases, etc.
Otros estudios han demostrado que la melatonina tiene diversas funciones y efectos sobre el estrés y trastornos relacionados con éste (Treatment of depression, anxiety, and sleep disorders (Cauffield et al. Prim Care Pract. May 1999, 3(3):290-304). Por su parte, Acuna-Castroviejo, et al. describen el tratamiento de fibromialgia con dosis de 3 mg de melatonina (Journal of Pineal Research 2006, 40(1), 989-9). 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).
También se han descrito factores comunes, como los trastornos del sueño en la depresión, ansiedad, fibromialgia y fatiga crónica, así como una relación entre estas distintas patologías, el estrés oxidativo y el sistema inmune (Hidalgo, Rev. Soc. Esp. Dolor, 2012, vol.19 no.2; Revuelta et al. Rev. Soc. Esp. Dolor 2010, vol.17 no.7; http://www.institutferran.org/fatiga_cronica.htm. 2017). 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).
Por otra parte, también relacionado con este tipo de patologías, se ha demostrado la intervención del zinc (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). 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).
En esta línea, en la patente US 2009/0017136 se da conocer el tratamiento de la fibromialgia y de la depresión con dosis de 200 mg de 5-Hidroxitriptófano (un precursor de la melatonina) y metionina-zinc a dosis de 30 mg; en US 2008/0107754 se describe una composición para mejorar el sueño que contiene, entre otros componentes, melatonina entre 0,3 y 0,6 mg y zinc entre 1 y 5 mg; en US 2015/0071993 se presenta una composición, también para inducir y mejorar el sueño, que contiene, entre otros componentes (extractos vegetales, vitaminas y magnesio) y melatonina y zinc a dosis de 3,0 mg y 25 mg, respectivamente. 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.
La melatonina ha sido formulada en distinto tipo de composiciones farmacéuticas y dietéticas, fundamentalmente para administración oral como comprimidos de ingestión directa, bucales, sublinguales y en algunos casos para administración nasal en forma de aerosoles y tanto para liberación inmediata como para liberación retardada o combinaciones de ambas. Las dos últimas, con el fin de conseguir un perfil similar a las concentraciones de melatonina que se presentan en el ritmo circadiano. 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.
Sin embargo, la biodisponibilidad oral de la melatonina en los distintos tipos de liberación es baja y presenta gran variabilidad (Benés et al. J. Pharmaceutical Sci. 1997, 86(10): 1115-1119), probablemente relacionado, además de con la ínter- variabilidad en pacientes, con la baja biodisponibilidad absoluta de aproximadamente un 15%, así como con el hecho de que la melatonina es ligeramente soluble (aprox. 0,15%). Ambos factores están muy relacionados, puesto que la cantidad de melatonina disponible como paso previo a su absorción (biodisponibilidad) depende de su solubilidad. 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. al. (J. Pineal Res., 2012; 52(4): 437-445) dan a conocer que diferentes formulaciones de melatonina oral han sido desarrolladas, incluyendo liberación inmediata, liberación controlada (sostenida) y liberación combinada (“surge-sustained release") y un gran número de dosis han sido usadas en ensayos clínicos con gran debate respecto al papel de las bajas dosis (0, 1-0,5 mg) y altas dosis (2-10mg) de melatonina. Presentándose una biodisponibilidad altamente variable, desde un 1% hasta un 74%. 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%.
En la patente US 2016/0166543 se describen formulaciones líquidas estables con una concentración de melatonina de hasta el 0,1 % utilizando dextrinas para su solubilización, a veces combinadas con concentraciones bajas de glicerina, como ayuda para el sueño. 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.
También en el documento WO 2016/058985 se describe una composición líquida para inyectables de melatonina, inicialmente libre de agua, basada en la solubilidad en alcohol y derivados polietoxilados para conseguir concentraciones de hasta el 10 % de melatonina; posteriormente esta solución es diluida en solución acuosa para su inyección. 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.
Las dosis típicas comercializadas en las formulaciones orales suelen ser de 2 mg a 5 mg, que se administran en una sola toma, tanto en liberación inmediata como en liberación controlada. En el mismo trabajo mencionado de Gooneratne et. al, se expone un estudio farmacocinético a doble-ciego en adultos con diferentes formulaciones orales de liberación combinada ("surge- sustained reléase”) desde baja dosis (0,4 mg) a alta dosis (4,0 mg) de melatonina. Se concluye que el estudio sugiere que la vida media, el Tmax (es decir, el tiempo al que se alcanza la máxima concentración (Cmax) en el plasma), el aclaramiento total y el volumen aparente de distribución, son similares para bajas y altas dosis y que es consistente con un comportamiento farmacéutico lineal. En el rango de bajas concentraciones ya se alcanzan 405+ 93 pg/ml (aprox. 4.000 pg/ml para altas dosis), valor substancialmente más alto que el nivel de melatonina fisiológico (alrededor de 40 pg/ml), lo que les lleva a sugerir que el uso de altas dosis de melatonina da lugar a una exposición marcadamente mucho más alta que la de los niveles fisiológicos, con el riesgo de una sobreexposición que puede persistir durante el resto de día. The 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 ("surge-sustained release") from low dose (0.4 mg) to high dose (4.0 mg) of melatonin. concludes that the study suggests that the half-life, Tmax (that is, 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 range of low concentrations, 405+ 93 pg / ml are already reached (approx. 4,000 pg / ml for high doses), a 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 than physiological levels, with the risk of overexposure that can persist for the rest of the day .
El interés por una composición terapéutica que combine la acción conjunta de la melatonina y el zinc se da a conocer en la patente ES 2 684 414 (Laboratorios Viñas, S.A.), en la que se presenta una formulación oral sólida en forma de comprimidos o cápsulas que contiene entre un 0,7 % y un 1,2 % de melatonina y entre un 7,0 % y un 12,0 % de zinc (en forma de sal de zinc, preferiblemente sulfato de zinc) para poder administrar dosis de 1,0 mg de melatonina y 10,0 mg de zinc. Se demuestra cómo el uso de melatonina micronizada permite una biodisponibilidad total en menos de 30 minutos, incluso a los 10 minutos, de la melatonina y de la sal de zinc. Sin embargo, esta formulación oral sólida no aporta ventajas cuando se trata de administrar melatonina y zinc a poblaciones que manifiestan dificultades en la deglución, como en población geriátrica, enfermos con determinadas enfermedades o en población infantil, particularmente en la población pediátrica, ya sea por tratarse de una forma oral sólida, por la limitación de la dosificación o por las características organolépticas, especialmente debido a la astringencia, la aspereza, el amargor y el sabor acre que presentan las sales de zinc. 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.
Por consiguiente, es manifiesto el interés y la necesidad de desarrollar soluciones técnicas que aporten composiciones orales, particularmente en la formulación conjunta de melatonina y zinc, que proporcionen cualidades farmacotécnicas que se caractericen por una biodisponibilidad alta, homogénea y reproducible de los principios activos, por la posibilidad de dosificación variable, por una ingesta sin dificultades en su deglución y con unas características organolépticas que no la hagan rechazable y que mantengan las estabilidad y las cualidades terapéuticas. 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.
Exposición de la Invención Invention Exhibition
La presente invención tiene por objeto una composición galénica, para uso oral, caracterizada por que está formulada como una solución líquida, comprende melatonina y una sal de zinc, presenta unas características organolépticas tolerables y permite una dosificación variable apta para el tratamiento de las alteraciones del sueño y de los estados de ánimo. 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.
Preferentemente la composición es en forma líquida estable. Preferably the composition is in stable liquid form.
La combinación de melatonina y zinc tiene la ventaja de poder proporcionar un efecto sinérgico, dada la manifestación de trastornos de sueño en distintos tipos de patologías: estado de ánimo, depresión, ansiedad, estrés, fatiga crónica y fibromialgia, y la incidencia de ambos activos en los procesos desencadenantes de dichas patologías. 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.
En relación con las cuestiones y complejidades anteriormente expuestas, los inventores de esta solicitud de patente han descubierto que es posible la obtención de formulaciones de melatonina a baja concentración y una sal de zinc en forma líquida estable, de liberación inmediata, reproducible y homogénea, con una biodisponibilidad del 100 %, tanto de la melatonina como del zinc, en el instante de su administración, puesto que ambos activos se administran disueltos. 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.
La melatonina tiene una solubilidad inferior al 0,2 % en agua, por lo que requiere el uso de cosolventes cuando se pretenden obtener concentraciones mayores. 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.
Las sales de zinc son particularmente conocidas por su sabor muy astringente, áspero, amargo y acre, especialmente el sulfato de zinc (Oral Zinc Sulfate Solutions Inhibit Sweet Taste Perception; Chem. Senses 29: 513-521, 2004). En general, son bastante solubles en agua, por lo que, normalmente, no presentan problemas de solubilización en cualquier forma galénica que tenga como vehículo mayoritario agua, manteniéndose en disolución total como paso previo a la absorción. Sin embargo, en presencia de disolventes o cosolventes orgánicos, como cuando se pretende enmascarar su sabor, o en combinación con otros activos insolubles en agua, sí presentan dificultades. Por ejemplo, el sulfato de zinc es insoluble en alcohol o escasamente soluble en glicoles. 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.
La combinación de melatonina y sales de zinc y, en particular, la combinación de melatonina y sulfato de zinc es compleja ya que se unen problemas de solubilización de los principios activos y problemas de enmascaramiento del sabor del sulfato de zinc. Así, debe tenerse en cuenta que: 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:
- la melatonina es ligeramente soluble en agua (< 0,2 %), pero es soluble en alcohol etílico (2- melatonin is slightly soluble in water (<0.2%), but it is soluble in ethyl alcohol (2
%); %);
- el sulfato de zinc monohidrato es bastante soluble en agua (35 %), ligeramente soluble en alcohol etílico (< 0,5 %) y escasamente soluble en glicerina (< 2 %); y - zinc sulfate monohydrate is fairly soluble in water (35%), slightly soluble in ethyl alcohol (<0.5%) and poorly soluble in glycerin (<2%); Y
- el sulfato de zinc, a concentraciones mayores del 0,1% en peso, respecto del peso total de la composición, tiene una elevada potencia inhibitoria del sabor dulce de diversos edulcorantes, lo que requiere el empleo de concentraciones elevadas de éstos. - 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.
Sin embargo, tras una experimentación con distintos vehículos disolventes y cosolventes, se ha observado que la combinación de agua, alcohol etílico (como cosolvente) y glicerina (como cosolvente y enmascarante de sabor), a pesar de las diferentes características de solubilidad de los activos y de la elevada potencia inhibitoria del sabor dulce por parte del sulfato de zinc, permite formular unas soluciones líquidas estables y organolépticamente muy tolerables. En particular determinadas relaciones molares y porcentuales entre activos, disolventes y cosolventes dan resultados particularmente ventajosos. Así, preferentemente: 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:
- el porcentaje de agua está entre el 30 % y el 45 % en peso, respecto del peso total de la composición (en lo sucesivo abreviado como “(p/p)”), preferiblemente entre el 35 % y el 40 % (p/p)· - 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)
- el porcentaje de alcohol etílico está entre el 5 % y el 10 % (p/p), preferiblemente entre el 7 % y el 9 % (p/p). - la relación molar entre el alcohol etílico y la melatonina está entre 85/1 y 115/1, preferiblemente entre 95/1 y 105/1. - 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.
- el porcentaje de glicerina es inferior al 55 % (p/p), preferiblemente entre el 45 % y el 50 % (p/p)· - the percentage of glycerin is less than 55% (w / w), preferably between 45% and 50% (w / w)
- el porcentaje de glicerina es superior entre un 5 % y 10 % (p/p) al porcentaje de agua. - the percentage of glycerin is higher between 5% and 10% (w / w) than the percentage of water.
- la relación molar entre glicerina y sulfato de zinc monohidrato está entre 35/1 y 45/1, preferiblemente entre 38/1 y 42/1. - the molar ratio between glycerin and zinc sulfate monohydrate is between 35/1 and 45/1, preferably between 38/1 and 42/1.
Asimismo, la presente invención propone una formulación líquida ventajosa al 0,5 % (5 mg/ml) en melatonina y al 1 % en zinc (10 mg/ml) que permite dosificar mediante gotero desde 0,25 mg/gota de melatonina y/o 0,5 mg/gota de zinc hasta las dosis habituales (2-5 mg) de melatonina y hasta 10 mg de zinc en volúmenes de ingesta de 1 mi (20 gotas) y, por consiguiente, de fácil dosificación y con características organolépticas tolerables, apropiada y deseable para población pediátrica y geriátrica o enfermos con dificultades de deglución de sólidos. 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.
La presente invención se refiere también al proceso de obtención de la formulación objeto de la patente. El estado, orden de adición y proporción de los componentes han sido desarrollados para permitir una formulación en forma líquida estable y organolépticamente tolerable. 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.
Es también objeto de la invención el uso de una composición farmacéutica de acuerdo con la invención para el tratamiento de las alteraciones del sueño y de los estados de ánimo. Another object of the invention is the use of a pharmaceutical composition according to the invention for the treatment of sleep and mood disorders.
Breve descripción de los dibujos Brief description of the drawings
Otras ventajas y características de la invención se aprecian a partir de la siguiente descripción, en la que, sin ningún carácter limitativo, se relatan unos modos preferentes de realización de la invención, haciendo mención de los dibujos que se acompañan. Las figuras muestran: Fig. 1, efecto del tratamiento con GV-340 en la métrica del sueño: (A) duración del sueño (horas: minutos), (B) tiempo de conciliación (minutos) y (C) evolución del número de despertares nocturnos. Total 38 casos. *p<0.001 entre basal y final. 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, efecto del tratamiento con GV-340 en el nivel de cansancio (A) y el estado de ánimo (B), antes y tras finalizar las 5 semanas de tratamiento. Total 38 casos. *p<0.001 entre basal y final. Fig. 2, effect of GV-340 treatment 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, juicios globales sobre la eficacia y la tolerabilidad del tratamiento con GV-340. (N =37) Fig. 3, global judgments on the efficacy and tolerability of GV-340 treatment. (N = 37)
Descripción detallada de unas formas de realización de la invención Detailed description of some embodiments of the invention
Una forma preferente de realización de la invención consiste en una composición galénica en forma líquida estable, para uso oral, de melatonina y de una sal de zinc, en una base diluyente y enmascarante de la astringencia, aspereza, amargor y acritud de la sal de zinc. 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.
La composición es para el tratamiento de alteración es del sueño y de los estados de ánimo. The composition is for the treatment of sleep disturbances and moods.
La composición puede presentarse en forma de solución líquida administrable con jeringa o gotero. The composition may be in the form of a liquid solution administrable with a syringe or dropper.
Los agentes activos de la formulación son la melatonina y una sal de zinc. The active agents in the formulation are melatonin and a zinc salt.
Ventajosamente la melatonina está presente a una concentración entre 0,4 % y 0,6 % en peso, respecto del peso total de la composición, preferentemente entre 0,43 % y 0,5 % en peso, respecto del peso total de la composición, y muy preferiblemente al 0,5 % en peso, respecto del peso total de la composición. Advantageously, melatonin is present at a concentration between 0.4% and 0.6% by weight, relative to the total weight of the composition, preferably between 0.43% and 0.5% by weight, relative to the total weight of the composition. , and most preferably 0.5% by weight, relative to the total weight of the composition.
Como sal de zinc pueden utilizarse preferentemente sales de zinc de ácidos orgánicos minerales, muy preferiblemente, muy preferentemente el sulfato de zinc monohidrato. Preferentemente la composición puede comprender entre el 0,8 % y el 1,1 % en peso de zinc respecto del peso total de la composición, de una sal de zinc, preferiblemente entre el 0,85 % y el 0,95 %. 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%.
Como vehículo de la formulación se prefiere una mezcla de agua, alcohol etílico y glicerina a determinadas relaciones porcentuales y molares entre activos, disolventes y cosolventes: 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:
- el porcentaje de agua se mantiene ventajosamente entre el 30 % y el 45 % (p/p), preferiblemente entre el 35 % y el 40 % (p/p). - the percentage of water is advantageously kept between 30% and 45% (w / w), preferably between 35% and 40% (w / w).
- el porcentaje de alcohol etílico como cosolvente está preferentemente entre el 5 % y el 10 % (p/p), y muy preferentemente entre el 7 % y el 9 % (p/p). - the percentage of ethyl alcohol as cosolvent is preferably between 5% and 10% (w / w), and most preferably between 7% and 9% (w / w).
- la relación molar entre el alcohol etílico y la melatonina está preferentemente entre 85/1 y 115/1, y muy preferiblemente entre 95/1 y 105/1. - 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.
- el porcentaje de glicerina es ventajosamente inferior al 55 % (p/p), y está preferiblemente entre el 45 % y el 50 % (p/p); - the percentage of glycerin is advantageously less than 55% (w / w), and is preferably between 45% and 50% (w / w);
- ventajosamente el porcentaje de glicerina es superior entre un 5 % y 10 % (p/p) al porcentaje de agua. - Advantageously, the percentage of glycerin is greater between 5% and 10% (w / w) than the percentage of water.
- preferentemente la relación molar entre la glicerina y el sulfato de zinc monohidrato estará entre 35/1 y 45/1, y muy preferiblemente entre 38/1 y 42/1. - 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.
Ventajosamente el pH de la solución se encuentra entre pH 4,0 y pH 7,0, preferiblemente entre pH 5,0 y pH 6,0. Advantageously the pH of the solution is between pH 4.0 and pH 7.0, preferably between pH 5.0 and pH 6.0.
Como agentes de ajuste y estabilizante del pH pueden utilizarse sales de ácidos orgánicos como el citrato sódico, el tartrato sódico, el acetato sódico o el sorbato potásico. La formulación puede contener otros aditivos complementarios de como edulcorantes, aromatizantes y saborizantes en cantidades inferiores al 1 %. 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%.
La invención también hace referencia al proceso de fabricación de la composición descrita en forma líquida. The invention also refers to the manufacturing process of the described composition in liquid form.
El proceso de fabricación se caracteriza por la incorporación y dilución secuencial en agua como base diluyente de la sal de zinc; la incorporación de la glicerina como cosolvente y enmascarante; la incorporación de la melatonina disuelta en alcohol etílico y la incorporación final del estabilizante de pH di suelto en agua. 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.
La incorporación de la glicerina debe realizarse a una velocidad de agitación entre 1.000 rpm y 2.000 rpm y a una velocidad de adición de manera que el tiempo mínimo para la incorporación total de la glicerina sea de 15 min y el tiempo máximo de 45 min. 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.
Una formulación ventajosa, obtenida en las condiciones descritas y con los componentes seleccionados, es una composición en forma líquida con una concentración al 0,5 % (5 mg/ml) en melatonina y al 1 % en zinc (10 mg/ml) que permite dosificar mediante gotero desde 0,25 mg/gota de melatonina y 0,5 mg/gota de zinc hasta las dosis habituales (2-5 mg) de melatonina y hasta 10 mg de zinc en volúmenes de ingesta de 1 mi (20 gotas) y, por consiguiente, de fácil dosificación y con características organolépticas tolerables, apropiada y deseable para población pediátrica y geriátrica o enfermos con dificultades de deglución de sólidos. 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 dosing by dropper from 0.25 mg / drop of melatonin and 0.5 mg / drop of zinc 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.
La composición puede presentarse en forma de solución líquida dosificable y administrable con jeringa o gotero. The composition may be presented in the form of a liquid dosable solution that can be administered with a syringe or dropper.
La invención también tiene por objeto el uso de una composición de acuerdo con la invención como preparado galénico líquido oral para el tratamiento de las alteraciones del sueño y de los estados de ánimo. Ejemplos 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
Ejemplo 1: Fórmula 1 Example 1: Formula 1
En un reactor de volumen adecuado para el volumen total final se adicionan 800 g de agua y se añaden, en agitación 54,5 g de sulfato de zinc monohidrato. La agitación se mantiene hasta la disolución total de la sal de zinc. 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.
Incorporar, manteniendo la agitación a 1.500 rpm 1.070 g de glicerina durante un tiempo de 30 min. Incorporate, keeping stirring at 1,500 rpm, 1,070 g of glycerin for 30 min.
Disolver en un equipo aparte 10 g de melatonina en 175 g de alcohol etílico y adicionar esta solución sobre la disolución anterior. Dissolve 10 g of melatonin in 175 g of ethyl alcohol in a separate kit and add this solution to the previous solution.
Disolver en un equipo aparte 4,0 g de sorbato potásico en 100 g de agua y adicionar esta solución sobre la disolución anterior. Dissolve 4.0 g of potassium sorbate in 100 g of water in a separate kit and add this solution to the previous solution.
Mantener la solución final en agitación durante 30 min Keep the final solution stirring for 30 min.
Estabilidad Stability
1 Objetivo 1. Objective
Se realiza el análisis químico de las muestras correspondientes a los 18 meses de estabilidad conservadas a 25 °C/60%HR y a 30 °C/65%HR del producto preparado según la Fórmula 1 mantenido en un envase primario: gotero de vidrio. 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. Características estudiadas y métodos de análisis 2. Characteristics studied and analysis methods
Se han realizado las siguientes determinaciones por el departamento de Desarrollo Analítico. pH The following determinations have been made by the Analytical Development department. pH
Color Colour
Sabor y olor Melatonina (% m/V) Taste and smell Melatonin (% m / V)
Sorbato potásico (% m/V) Potassium sorbate (% m / V)
SSRR de melatonina (5-Metoxitriptamina y N-Acetil 5-hidroxitriptamina). (*): no se determina el contenido de Zn en este punto de estabilidad ya que no es un parámetro susceptible a cambiar a lo largo del tiempo, no es un parámetro indicativo de estabilidad. 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. Resultados En las siguientes tablas se presentan los resultados obtenidos: □ pH:
Figure imgf000015_0001
3. Results The following tables show the results obtained: □ pH:
Figure imgf000015_0001
□ Color:
Figure imgf000015_0002
□ Sabor y olor:
Figure imgf000016_0001
□ Color:
Figure imgf000015_0002
□ Taste and smell:
Figure imgf000016_0001
□ Zn2+ (% m/V):
Figure imgf000016_0002
□ Zn 2+ (% m / V):
Figure imgf000016_0002
No se determina el contenido de Zn a partir de los 6 meses ya que no es un parámetro susceptible a cambiar a lo largo del tiempo, no es un parámetro indicativo de estabilidad. 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.
□ Melatonina (% m/V):
Figure imgf000016_0003
□ Sorbato potásico (% m/V):
Figure imgf000017_0001
□ Melatonin (% m / V):
Figure imgf000016_0003
□ Potassium sorbate (% m / V):
Figure imgf000017_0001
□ Sustancias relacionas de melatonina (% respecto melatonina'):
Figure imgf000017_0002
□ Related substances of melatonin (% with respect to melatonin ' ):
Figure imgf000017_0002
Durante el estudio de estabilidad se observa que: During the stability study it is observed that:
□ pH: se mantiene en las dos condiciones de conservación. □ pH: it is maintained in the two conditions of conservation.
□ Color: el producto no cambia significativamente de color a lo largo del tiempo en ninguna de las dos condiciones de conservación estudiadas. □ Color: the product does not change significantly in color over time under either of the two storage conditions studied.
□ Sabor y olor: el producto no cambia significativamente de olor ni de sabor a lo largo del tiempo en ninguna de las dos condiciones estudiadas: sabor y olor aceptables y tolerables. □ 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.
□ Melatonina: la concentración se mantiene dentro de los límites de aceptación y no ha variado ni con el tiempo ni con las condiciones de almacenamiento. □ Sorbato potásico: la concentración se mantiene dentro de los límites de aceptación y no ha variado ni con el tiempo ni con las condiciones de almacenamiento. □ 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 de la melatonina: en las muestras correspondientes a los 18 meses de estabilidad no se detecta ninguna sustancia relacionada superior a los límites de aceptación. □ SSRR of melatonin: in the samples corresponding to the 18 months of stability, no related substances are detected above the acceptance limits.
4. Conclusión 4. Conclusion
Las muestras de la Fórmula 1 son estables durante 18 meses conservadas a 25°C/60%HR y a 30°C/65%HR. Formula 1 samples are stable for 18 months stored at 25 ° C / 60% RH and at 30 ° C / 65% RH.
Estudio clínico Clinical study
“Estudio de Aceptabilidad Organoléptica, Tolerabilidad y Eficacia del Preparado GV- 340(*) en Insomnio con Decaimiento” (2018-2019). "Study of Organoleptic Acceptability, Tolerability and Efficacy of the Preparation GV-340 (*) in Insomnia with Decay" (2018-2019).
Departamento de Investigación Clínica. Laboratorios Viñas, S.A. Department of Clinical Research. Laboratorios Viñas, S.A.
(*) GV-340 hacer referencia la Fórmula 1 descrita en este documento. (*) GV-340 refer to Formula 1 described in this document.
Objetivo: Valorar la aceptabilidad organoléptica, la tolerabilidad y la eficacia de la solución de GV-340 en gotas en pacientes con insomnio y decaimiento asociado. Objective: To assess the organoleptic acceptability, tolerability and efficacy of the GV-340 drop solution in patients with insomnia and associated decay.
Metodología: Selección de los voluntarios según criterio médico. Fueron criterios de inclusión ser mayor de edad y presentar insomnio con decaimiento. Fueron criterios de exclusión el uso concomitante de productos similares o benzodiacepinas, usuarios habituales de melatonina, o embarazo/lactancia. La duración prevista del tratamiento en estudio fue de 4 a 5 semanas. Se propuso una toma diaria de 8 gotas (2 mg de melatonina y 4 mg de zinc), unos 30 min antes de acostarse. 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.
Resultados: Participaron 13 investigadores que incluyeron 38 casos con insomnio con decaimiento asociado. La distribución por sexo fue de 27 mujeres y 11 hombres con una edad media de 56 ± 17 años. Los perfiles más habituales fueron insomnio de conciliación, de mantenimiento, o una combinación de ambos. En promedio, cada caso se administró 8.1 ± 0.4 gotas/día, durante 4.9 ± 2.2 semanas. Al final del estudio con el GV-340 la calidad del sueño mejoró en el 76% de los 38 casos. La duración del sueño aumentó en 46 minutos, de media, cada noche (Figura 1 A). El tiempo de conciliación se redujo 2 veces (Figura IB), los despertares nocturnos remitieron en el 42% de los casos, y se redujeron un 30% en los que aun presentaban al final del estudio (Figura 1C). 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 IB), 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).
El tratamiento GV-340 a base de melatonina y zinc en gotas, mejora la métrica del sueño reduciendo el tiempo de conciliación y el número de despertares, aumentando el tiempo de descanso, a través de un sueño reparador que, junto al papel del zinc presente en la fórmula, contribuye a una mejora en el estado de ánimo del paciente (Figura 2). Estos resultados de acompañan de una excelente aceptabilidad, tolerabilidad y perfil de seguridad. El 89% de los pacientes opinó que continuaría con el tratamiento. 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 believed that they would continue with the treatment.
Tabla 1. Aceptabilidad organoléptica del GV-340 Table 1. Organoleptic acceptability of GV-340
Promedio Desv. Est. Average Dev. Its T.
Sabor L8 2L Flavor L8 2L
Olor 7.9 2.1 Odor 7.9 2.1
Facilidad administración Ease of administration
8.7 1.2 8.7 1.2
(recuento gotas) (count drops)

Claims

REI VINDIC ACIONE S REI VINDIC ATION S
1 - Composición galénica, para uso oral, en forma líquida, caracterizada por que comprende entre 0,4 % y 0,6 % en peso, respecto del peso total de la composición, de melatonina y entre 0,8 % y el 1,1 % en peso de zinc, respecto del peso total de la composición, de una sal de zinc. 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 - Composición según la reivindicación 1, caracterizada porque comprende entre 0,43 % y 0,5 % en peso, respecto del peso total de la composición, de melatonina. 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 - Composición según una de las reivindicaciones 1 ó 2, caracterizada porque comprende entre 0,85 % y el 0,95 % en peso de zinc, respecto del peso total de la composición, de una sal de zinc. 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 - Composición según cualquiera de las reivindicaciones 1 a 3, caracterizada porque la sal de zinc es una sal de ácidos orgánicos o una sal mineral. 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 - Composición según la reivindicación 4, caracterizada porque la sal de zinc es el sulfato de zinc monohidrato. 5 - Composition according to claim 4, characterized in that the zinc salt is zinc sulfate monohydrate.
6 - Composición según cualquiera de las reivindicaciones 1 a 5, caracterizada porque la composición comprende una base diluyente formada por una mezcla de agua, alcohol etílico y glicerina. 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 - Composición según la reivindicación 6 caracterizada porque comprende un porcentaje de agua entre el 30 % y el 45 % en peso, respecto del peso total de la composición, preferiblemente entre el 35 % y el 40 % en peso, respecto del peso total de la composición. 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 - Composición según una de las reivindicaciones 6 ó 7, caracterizada porque comprende un porcentaje de alcohol etílico entre el 5 % y el 10 % en peso, respecto del peso total de la composición, preferiblemente entre el 7 % y el 9 % en peso, respecto del peso total de la composición. 9 - Composición según cualquiera de las reivindicaciones 6 a 8, caracterizada porque la relación molar entre el alcohol etílico y la melatonina está entre el 85/1 y el 115/1, preferiblemente entre 95/1 y 105/1. 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 - Composición según cualquiera de las reivindicaciones 6 a 9, caracterizada porque comprende un porcentaje de glicerina inferior al 55 % en peso, respecto del peso total de la composición, preferiblemente comprende un porcentaje de glicerina entre el 45 % y el 50 % en peso, respecto del peso total de la composición. 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 - Composición según cualquiera de las reivindicaciones 6 a 10, caracterizada porque el porcentaje de glicerina es superior entre un 5 % y 10 % en peso, respecto del peso total de la composición, al porcentaje de agua. 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 - Composición según cualquiera de las reivindicaciones 6 a 11, caracterizada porque la relación molar entre la glicerina y el sulfato de zinc monohidrato está entre el 35/1 y el 45/1, preferiblemente entre el 38/1 y el 42/1. 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 - Composición según cualquiera de las reivindicaciones 1 a 12, caracterizada porque el pH de la solución está comprendido entre 4,0 y 7,0, preferiblemente entre 5,0 y 6,0. 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 - Composición según cualquiera de las reivindicaciones 1 a 13, caracterizada porque comprende una sal de ácido orgánico como agente de ajuste y estabilizante del pH, preferiblemente del grupo formado por citrato sódico, tartrato sódico, acetato sódico y el sorbato potásico. 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 - Composición según cualquiera de las reivindicaciones 1 a 14, caracterizada porque la composición se presenta en forma de solución líquida dosifí cable y administrable con jeringa o gotero. 15 - Composition according to any of claims 1 to 14, characterized in that the composition is presented in the form of a liquid solution dosifí cable and can be administered with a syringe or dropper.
16 - Composición según cualquiera de las reivindicaciones 1 a 15, caracterizada porque está envasada en un frasco con un gotero apto para dosificar una cantidad de 0,25 mg/gota de melatonina. 17 - Composición según cualquiera de las reivindicaciones 1 a 15, caracterizada porque está envasada en un frasco con un gotero apto para dosificar una cantidad de 0,25 mg/gota de melatonina y 0,5 mg/gota de zinc. 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 - Método para preparar una composición galénica oral líquida de acuerdo con cualquiera de las reivindicaciones 1 a 17, caracterizado porque comprende las etapas de: 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] incorporación y disolución de la sal de zinc en agua; [b] incorporación de glicerina en la disolución obtenida en la etapa [a]; [a] incorporation and dissolution of the zinc salt in water; [b] incorporation of glycerin in the solution obtained in step [a];
[c] disolución de la melatonina en alcohol etílico; e [c] dissolution of melatonin in ethyl alcohol; and
[d] incorporación de la disolución obtenida en la etapa [c] en la disolución obtenida en la etapa[d] incorporation of the solution obtained in step [c] in the solution obtained in step
[b] 19 - Método según la reivindicación 18, caracterizado porque la etapa [b] de incorporación de la glicerina en la solución obtenida en la etapa [a] tiene una duración comprendida entre 15 y 45 minutos. [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 - Método según una de las reivindicaciones 18 ó 19, caracterizado porque comprende, adicionalmente, las siguientes etapas: 20 - Method according to one of claims 18 or 19, characterized in that it additionally comprises the following steps:
[e] disolución del estabilizante de pH en agua; e [e] dissolving the pH stabilizer in water; and
[f incorporación de la disolución obtenida en la etapa [e] en la disolución obtenida en la etapa [d] [f incorporation of the solution obtained in step [e] in the solution obtained in step [d]
21 - Uso de una composición galénica según cualquiera de las reivindicaciones 1 a 17 como preparado galénico oral líquido para el tratamiento de las alteraciones del sueño y de los estados de ánimo. 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.
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