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    • 专利摘要:
    Galenic composition, for oral use, comprising micronized melatonin and a zinc salt and corresponding method and use. The subject of the invention is a galenic composition, for oral use, comprising micronized melatonin and a zinc salt, suitable for the treatment of sleep disturbances. The composition preferably comprises between 0.7% and 1.2% by weight relative to the total weight of the composition and advantageously at least 99% of the micronized melatonin particles have a particle size of less than 30 microns. In the method for preparing the composition, micronized melatonin is formulated by incorporation and sequential dilution in the diluent base and the incorporation and final sequential dilution of the zinc salt in the homogenous mixture of micronized melatonin and the diluent base. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2684414A1
    申请号:ES201730558
    申请日:2017-03-31
    公开日:2018-10-02
    发明作者:Antonio VIÑAS BUXADÉ；Antonio Conchillo Teruel；Miguel CÁNOVAS UBERA
    申请人:Laboratorios Vinas SA；
    IPC主号:
    专利说明:

    image 1
    GALENIC COMPOSITION, FOR ORAL USE, THAT INCLUDES MICRONIZED MELATONIN AND A ZINC SALT AND CORRESPONDING METHOD AND USE 5 DESCRIPTION
    Field of the Invention
    The present invention describes a galenic composition in stable solid form, of
    10 Micronized melatonin and a zinc salt, useful for the treatment of sleep disorders. The invention also relates to a method for preparing the composition according to the invention and a use thereof. State of the art
    15 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 fulfilling professional, family or social obligations.
    These disorders, which occur in the form of a little restful sleep or of
    20 disorders in the rhythm and in the amount of sleep or as an inverted dream or daytime sleep, are denominated according to their manifestations as: insomnia, hypersomnia, narcolepsy, snoring and sleep apnea, parasomnias and other disorders, leg syndrome restless, night terrors, nightmares and sleepwalking, etc.
    25 Its origin is very varied, the cause or symptom consideration 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 sleep rhythm 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, 5 which is regulated by external signals from the environment, to which the most potent is exposure to light-darkness. The light is perceived by the retina, modulates the synthesis of melatonin ("hormone of darkness") and helps synchronize the internal clock and the natural alternation day-night, so that artificial light and the moment of its exposure can modify The neurohormone production pattern
    10 Melatonin and affect sleep, which has been correlated with its plasma levels.
    The main clinical disorders related to circadian rhythm or plasma levels of Melatonin include: sleep phase delay syndrome, sleep phase advance syndrome, sleep rhythm disorder
    15 irregular wakefulness, sleep-wake cycle disorder different from 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; the
    20 levels typically increase at the beginning of the dark, reaching a maximum at midnight, between 23 and 3 in the morning. Currently, the pharmaceutical compositions are administered at usual doses between 2 mg and 5 mg, in the form of tablets, capsules, liquids, etc.
    25 On the other hand, Melatonin, in addition to the regulation of the circadian cycle, participates in a wide variety of pathophysiological processes, including the regulation of the immune system and the endogenous antioxidant system.
    image2
    Also, it is a proven fact that Melatonin levels decrease with age and that this deficiency is associated with insomnia, depression, anxiety and stress.
    Also, recent research has linked low levels of melatonin
    5 with aging and with the development of neurodegenerative diseases (Bubenik et al., J. Physiol. Pharmacol. 2011, 62, 13-19). For example, document US2006 / 0257502 discloses a combination (more than ten) of antioxidant mitochondrial nutrients, including Melatonin at a dose of 0.1 to 3 mg, to prevent and improve disorders related to stress and the
    10 oxidative damage, such as depression, chronic fatigue syndrome, 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. Prime Care Pract. May 1999, 3 (3): 290- 304);
    15 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.
    20 Pain, 20012, vol.19 no.2; Revuelta et al. Rev. Soc. Esp. Dolor 2010, vol.17 no.7; http://www.institutferran.org/fatiga_cronica.htm, 2017).
    On the other hand, also related to this type of pathologies, Zinc intervention has been demonstrated (Mlyniec et al. Journal of Affective Disorders 2015, 174, 89
    25 100; Maywald et al. Journal of Trace Elementt in Medicine and Biology 29 (2015) 24-30; Maares et al. Archives of Biochemistry and Biophysics 2016, 1-8; Npwak et al. Pharmacological Reports 2015, 67, 659-662).
    image3
    Along these lines, the treatment of fibromyalgia and depression with a 200 mg dose of 5-Hydroxytryptophan (a precursor of Melatonin) and Methionine-Zinc at a dose of 30 mg is disclosed in US Pat. US2008 / 0107754 describes a composition to improve the sleep it contains, among others
    5 components, Melatonin between 0.3 and 0.6 mg and Zinc between 1 and 5 mg; In US2015 / 0071993 a composition is presented, 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 compositions and
    10 dietary, mainly for oral administration as direct ingestion tablets, buccal, sublingual and in some cases for nasal administration in the form of aerosols and, both for immediate release, as for delayed release or combinations of both. The last two, in order to achieve a profile similar to the concentrations of Melatonin that occur in the rhythm
    15 circadian.
    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 inter
    20 variability in patients, with the low absolute bioavailability of approximately 15%, as well as with the fact that Melatonin is slightly soluble (approx. 0.15%). Both factors are closely related, since the amount of Melatonin available as a previous step to its absorption (bioavailability) depends on its solubility.
    25 Gooneratne et. to the. (J. Pineal Res., 2012; 52 (4): 437-445) disclose that different formulations of oral Melatonin have been developed, including immediate release, controlled release (sustained) and combined release (“surgesustained release”) and a large number of doses have been used in clinical trials
    30 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%.
    image4
    Typical doses marketed in oral formulations are usually 2 mg to 5.5 mg, which are administered in a single dose, both in immediate release and in controlled release.
    In the same work mentioned by Gooneratne et. At the same time, a double-blind pharmacokinetic study is presented in adults with different oral formulations of "combined-sustained 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, the Tmax (that is, the time at which the maximum concentration (Cmax) in the plasma is reached), the total clearance and the apparent volume of distribution, are similar for low and high dose and that is consistent with a linear pharmaceutical behavior 15. In the range of low concentrations already reached 405+ 93 pg / ml (approx.
    4,000 pg / ml for high doses), a value substantially higher than the level of physiological Melatonin (around 40 pg / ml), which leads them to suggest that the use of high doses of Melatonin results in markedly much more exposure high than that of physiological levels, with the risk of overexposure that
    20 may persist for the rest of the day.
    Therefore, the need to develop technical solutions that provide oral compositions and that provide pharmacotherapeutic qualities that are characterized by a homogeneous and reproducible solubilization of Melatonin is manifest,
    25 combined or not, in order to overcome the first stage prior to its absorption and maintain the therapeutic qualities.
    image5 Exhibition of the Invention
    The present invention aims at a galenic composition, for oral use, characterized in that it comprises micronized Melatonin and a zinc salt, suitable for the treatment of sleep disturbances.
    Preferably the composition is in stable solid form.
    The combination of Melatonin and Zinc has the advantage of being able to provide a
    10 synergistic effect, given the manifestation of sleep disorders in different types of pathologies: depression, anxiety, stress, chronic fatigue and fibromyalgia, and the incidence of both active agents in the triggering processes of these pathologies.
    In relation to the issues and complexities set forth above, the
    15 inventors of this patent application have discovered that it is possible to obtain formulations of Melatonin at low concentration and a stable zinc salt in a stable, immediate, reproducible and homogeneous form, with a solubilization greater than 85% of Melatonin and of zinc salt in less than 30 minutes.
    Zinc salts, in general, are quite soluble in aqueous solutions, as is the case with those described in this invention, so that they do not normally have solubilization problems in any galenic form that are developed, keeping in total dissolution as previous step to absorption.
    On the contrary, in products of low solubility there is an important relationship between particle size and solubilization time. The average size of the synthetic Melatonin particles is usually greater than 100 microns, but in sustained-release formulations this problem is overcome by a previous dissolution of Melatonin before being incorporated into the encapsulation or in
    30 the polymers used.

    The present invention proposes the use of micronized Melatonin in immediate or sustained release formulations in order to achieve oral compositions that exhibit faster and more homogeneous solubilization from a Melatonin of
    5 smaller particle range and exposed to the solubilization medium, narrower and more homogeneous.
    Likewise, the present invention proposes advantageous formulations that combine lower doses than usual (2-5 mg) with micronized Melatonin at a certain range that allow to reach the practically fully solubilized product, as a step prior to its absorption, in a short time.
    The present invention also relates to the process of obtaining the formulation object of the patent. The state, combination and proportion of the components have
    15 have been developed to allow a stable solid formulation capable of releasing the active components immediately, reproducibly and homogeneously, with a solubilization greater than 85% of the active ingredients in less than 30 minutes.
    The use of a pharmaceutical composition according to the invention for the treatment of sleep disorders is also an object of the invention. Detailed description of embodiments of the invention
    A preferred embodiment of the invention consists of a galenic composition in stable solid form, for oral use, of micronized Melatonin and of a zinc salt, in a diluent base and a lubricant.
    30 The composition is for the treatment of sleep disorders.
    image6
    The composition may be presented as tablets or encapsulated in hard gelatin capsules.
    5 The active agents of the formulation are Melatonin and a zinc salt.
    Melatonin is micronized Melatonin and the concentration at which it may be present is, advantageously between 0.7% and 1.2% by weight with respect to the total weight of the composition, preferably between 0.82% and 1.0% .
    Advantageously at least 99% of the micronized melatonin particles have a particle size of less than 30 microns, and preferably at least 99% of the particles have a size smaller than 20 microns and 90% have a smaller size at 10 microns
    As zinc salt, preferably zinc salts of organic acids of less than 3 carbon atoms, most preferably zinc acetate, or soluble mineral salts (anhydrous or hydrated), such as zinc chloride or zinc sulfate, and most preferably Zinc Sulfate monohydrate.
    The composition preferably comprises between 7.0% and 12.0% by weight of Zinc with respect to the total weight of the composition, of a zinc salt, preferably between 8.2% and 10.0%.
    The particle size of the zinc salt is advantageously less than 300 microns, preferably less than 250 microns.
    As diluent base, polysaccharides or monosaccharides (or mixtures of the foregoing) are preferred. Advantageously, the diluent base is a base of the group consisting of Dextrose, Lactose, Isomalt or Fructose, and preferably is Isomalt.
    image7
    Preferably the galenic composition of the present invention is compressed or encapsulated in order to obtain a tablet or a capsule. Advantageously the tablet or capsule has an amount equivalent to 1.0 mg of Melatonin.
    5 micronized and an amount equivalent to 10.0 mg of Zinc.
    The invention also refers to the manufacturing process of the composition described in solid form of immediate, homogeneous and reproducible release of Melatonin.
    The manufacturing process is characterized by the use of micronized Melatonin formulated by incorporation and sequential dilution in the diluent base and the final sequential incorporation and dilution of the Zinc salt in the homogeneous mixture of micronized Melatonin and the diluent base (which is preferably Isomalt)
    An advantageous formulation, obtained under the conditions described and with the selected components, is a composition in solid form with a concentration in micronized Melatonin between 0.82% and 1.0% and a final concentration in zinc salt between 8.2% and 10.0%.
    The object of the invention is also the use of a composition according to the invention as an oral galenic preparation for the treatment of sleep disorders. 25 Solubilization Study of Micronized Melatonin vs. Melatonin
    A total solubilization time test of micronized Melatonin against Melatonin in aqueous medium, at a concentration of 0.13% and at a different pH, has been carried out.
    30
    image8
    The results are shown in the following table:
    Water pH 1pH 4pH 7pH 9
    Melatonin Average size 150 microns > 30 min> 30 min> 30 min> 30 min> 30 min
    Micronized melatonin 90% <10 microns <10 min<10 min<10 min<10 min<10 min
    The results demonstrate the advantage of the use of micronized Melatonin for the formulation of a solid immediate release formula object of the invention. Examples
    Example 1: Formula 1
    10 In a V-mixer, add 36.3 g of Isomalt and add the micronized Melatonin. Mix for at least 10 minutes.
    Sequentially incorporate each of the following Isomalt fractions: 36.2 g, 72.3 g, 180.9 g, 296.6 g, 53.2 g and 53.2 g ,. mixing, for at least 10 minutes, the mixture with each fraction.
    Sequentially incorporate each of the following Zinc Sulfate fractions: 127.0 g and 127.5 g. mixing at least for 10 minutes the mixture with every 20 fraction,
    Add the Magnesium Stearate and mix for at least 10 minutes.
    image9
    Example 2: Formula 2
    In a V mixer, add 36.3 g of Isomalt and add Melatonin. Mix for at least 10 minutes.
    5 Sequentially incorporate each of the following Isomalt fractions: 36.2 g, 72.3 g, 180.9 g, 296.6 g, 53.2 g and 53.2 g. , mixing, at least, for 10 minutes the mixture with each fraction.
    10 Sequentially incorporate each of the following Zinc Sulfate fractions: 127.0 g and 127.5 g. , mixing, for at least 10 minutes, the mixture with each fraction,
    Add the Magnesium Stearate and mix for at least 10 minutes. 15 Table 1
    Formulation 1 Formulation 2
    Isomatous 728.6 g728.6 g
    Micronized melatonin 9.0 g
    Melatonin 9.0 g
    Zinc salt 254.5 g254.5 g
    Magnesium stearate 7.8 g7.8 g
    Total 1,000 g1,000 g Dissolution Speed and Homogeneity Test
    Dissolution medium: cuvettes with 900 ml of 0.1 M HCl Stirring: 50 rpm

    Temperature: 37.0 ºC + 0.5 ºC Time: 30 minutes Equipment: Paddles
    5 1 capsule is placed in each cuvette.
    After 30 minutes, an aliquot of each cuvette is taken and filtered through a pleated paper filter (Whatman 2V 150 nm).
    The filtered solution is chromatographed by HPLC to determine the amount of dissolved Melatonin versus the Melatonin standard.
    Results
    15 The following table shows the results in% of Melatonin versus theoretical (100%) obtained from 6 samples taken from each of the formulations.
    Unity Formulation 1Formulation 2
    one 98.473.2
    2 95.579.2
    3 100.367.2
    4 97.581.6
    5 100.274.4
    6 92.985.5
    The results show a practically total and homogeneous solubilization and release in formula 1 (Micronized Melatonin), while in formula 2 there is no total release at 30 minutes and the release that occurs is less homogeneous.
    image10 Stability
    In table 2, the results of the stability tests of the above formulation 1 carried out at a temperature of 25 ° C at 7 months after its formulation are attached.
    Table 2
    Formula 1
    10 Results of the stability study at 25 ºC / 60% RH Start date of the study: 07/14/2016
    Date of analysis Specifications for product release06/13/201601/30/17
    Days since study start weatherweather
    Months since study start 0 months7 months
    Appearance capsules Hard gelatin capsules of size # 3, opaque, with a lilac colored lid and body.RightRight
    Appearance Powder White granular-looking toilet powderRightRight
    Disintegration (36 ºC -38 ºC) <30 minutesApprox. 5 minApprox. 6 min
    ZnSO4 H2O (mg / capsule) Complexometry 24.7 -30.226.027.22
    Melatonin (mg / capsule) UV-Vis 0.90 -1.100.9530.961
    SSRR Melatonin (% compared to Melatonin)
    5-Methoxytryptamine ≤ 0.5n.r.n.d.
    Other singles ≤ 0.1n.r.n.d.
    Sum of other individuals ≤ 1.0n.r.n.d.
    n.r .: not done;
    n.d .: not detected SSRR: Related Substances (impurities with more or less similar structure). Other individuals: other SSRRs, whose structure is unknown but is
    15 detected with the method used and assigned a specification. Add other singles: It is a specification for the total content of impurities determined as “other singles”
    image11
    The stability results show how the formulations described are stable for a prolonged period of time (at least 7 months) at room temperature (25 ° C); both in relation to the active substance and to the galenic characteristics of the formulation.
    权利要求:
    Claims (1)
    [1]
    image 1
    1-Galenic composition, for oral use, characterized in that it comprises micronized Melatonin and a zinc salt, suitable for the treatment of the 5 sleep disorders.
    2 - Composition according to claim 1, characterized in that it comprises between 0.7% and 1.2% by weight with respect to the total weight of the micronized Melatonin composition, preferably between 0.82% and 1.0%.
    Composition according to one of claims 1 or 2, characterized in that at least 99% of the micronized melatonin particles have a particle size of less than 30 microns, and preferably at least 99% of the particles have a size less than 20 microns and 90% have a smaller size
    15 at 10 microns.
    4 -Composition according to any of claims 1 to 3, characterized in that it comprises between 7.0% and 12.0% by weight of Zinc with respect to the total weight of the composition, of a zinc salt, preferably between 8.2 % and 10.0%.
    Composition according to any one of claims 1 to 4, characterized in that the zinc salt is an organic acid salt of less than 3 carbon atoms or a soluble, anhydrous or hydrated mineral salt.
    Composition according to claim 5, characterized in that the zinc salt is zinc acetate.
    7. Composition according to claim 5, characterized in that the soluble mineral salt is a salt of the group formed by zinc chloride or zinc sulfate. 30
    image2
    8 -Composition according to claim 5, characterized in that the zinc salt is Zinc Sulfate monohydrate.
    9. Composition according to any of claims 4 to 8, characterized in that the particle size of the zinc salt is less than 300 microns, preferably less than 250 microns.
    Composition according to any one of claims 1 to 9, characterized in that the composition comprises a diluent base of the group consisting of 10 polysaccharides, monosaccharides and mixtures of the foregoing.
    Composition according to claim 10, characterized in that said diluent base is a base of the group consisting of Dextrose, Lactose, Isomalt and Fructose, and is preferably Isomalt.
    Composition according to any one of claims 1 to 11, characterized in that it forms a capsule or a tablet containing an amount equivalent to 1.0 mg of micronized Melatonin and an amount equivalent to 10.0 mg of Zinc.
    13 - Method for preparing an oral galenic composition according to any of claims 1 to 12, characterized in that the micronized Melatonin is formulated by incorporation and sequential dilution in the diluent base and the incorporation and final sequential dilution of the zinc salt in the homogeneous mixture
    25 of micronized Melatonin and the diluent base.
    14 - Method according to claim 13, characterized in that the micronized Melatonin and Zinc salt are formulated in a solid form of immediate, homogeneous and reproducible release of Melatonin.
    30
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    同族专利:
    公开号 | 公开日
    ES2684414B1|2019-12-11|
    引用文献:
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    US6620836B1|1997-01-22|2003-09-16|Jay Patrick|Antiarrhythmic and tranquilizer composition and treatment|
    CN1332971A|2000-07-09|2002-01-30|鄂来明|Melatonin milk products|
    US20070196348A1|2006-02-23|2007-08-23|Gardiner Paul T|Compositions and methods for the induction and maintenance of quality sleep|
    US20080107754A1|2006-11-08|2008-05-08|Jeff Luciano|Dietary supplement and a method to enhance sleep and lucid dreaming|
    US20080254121A1|2007-04-10|2008-10-16|Iomedix Sleep International Srl|Multi-layer melatonin composition|
    US20100120887A1|2007-05-24|2010-05-13|The Trustees Of Columbia University In The City Of New York|Sustained release formulation of melatonin|
    US20150071993A1|2013-09-10|2015-03-12|Creative Medical Health Inc.|Compositions and Methods for Improving Sleep Using A Nutraceutical Formulation|
    EP3127536A1|2015-08-05|2017-02-08|Versailles B.V.|Melatonin formulations and methods for preparation and use|
    CN105106201A|2015-09-17|2015-12-02|福建省幸福生物科技有限公司|Melatonin healthcare capsule for improving sleeping|WO2020150605A1|2019-01-18|2020-07-23|Physician's Seal, LLC|Solid micronized melatonin composition|
    WO2021136862A1|2019-12-31|2021-07-08|Laboratorios Viñas S.A.|Liquid galenic composition for oral use comprising melatonin and a zinc salt, and corresponding method and use|
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