Aqueous Melatonin Formulations

Abstract

The present invention relates to aqueous melatonin formulations that are free of unnecessary excipients and potentially harmful substances. In particular, the present invention relates to aqueous melatonin compositions that contain potassium sorbate as the only preservative.

Description

[Technical field]

[0001] The present invention relates to aqueous melatonin formulations that are free of unnecessary excipients and potentially harmful substances. In particular, the present invention relates to aqueous melatonin compositions that contain potassium sorbate as the only preservative. [Background technology]

[0002] Sleep disorders continually affect hundreds of millions of people worldwide, many of whom suffer from negative impacts on quality of life, lack of productivity, and high healthcare utilization. The most common sleep disorder is insomnia, or more literally, the inability to sleep. Insomnia has a variety of etiologies and severity and is estimated to affect up to 6-12% of the adult population and as many as 15-25% of children. Thus, there is a great need to provide treatment for sleep disorders.

[0003] Traditionally, synthetic hypnotic drugs such as barbiturates and later benzodiazepines and quinazolinones have been used to induce sleep. A Benzodiazepines, which enhance the effects of the neurotransmitter gamma-aminobutyric acid (GABA) at receptors, are prescribed to individuals suffering from sleep disorders. However, due to the risk of dependence, daytime sedation, and respiratory depression, long-term use of benzodiazepines is not recommended, and at best only intermittent administration at the lowest effective doses is recommended. Benzodiazepines also generally worsen sleep quality by increasing light sleep and decreasing deep sleep.

[0004] In response to safety concerns surrounding benzodiazepines, non-benzodiazepine hypnotics (or so-called Z-drugs) were introduced in the early 1990s. These drugs are "benzodiazepine-like" in nature and exhibit a similar pharmacodynamic profile. Although the use of non-benzodiazepines has become more common, their purported improved efficacy remains controversial, and side effects similar to those of benzodiazepines are frequent.

[0005] In contrast to synthetic hypnotics, melatonin is a naturally occurring indole hormone released by the pineal gland located in the brain. It is released primarily at night, and it is well established that melatonin is involved in the regulation of circadian rhythms that regulate the sleep-wake cycle, asserting its effects primarily through its interaction with melatonin receptors. Melatonin has also been found to regulate sleep patterns related to seasonal cycles.

[0006] Melatonin is a neurohormone with the chemical identity N-acetyl-5-methoxytryptamine, and is made from tryptophan via serotonin as an intermediate. In the past, melatonin was derived from bovine pineal tissue, but today it is primarily synthetic, which limits the risk of contamination or the means of transmitting infectious material.

[0007] The use of melatonin to induce sleep has several advantages over conventional synthetic hypnotics. First, melatonin is naturally metabolized and blood levels return to normal daytime levels within 6-8 hours of administration. Thus, melatonin does not, in many cases, cause adverse effects the day after administration, as is the problem with conventional hypnotics. Importantly, melatonin does not present the same risk of addiction as conventional hypnotics, and being a naturally occurring endogenous compound, it does not induce amnesic effects like benzodiazepines.

[0008] Given the many benefits of melatonin as a sleep inducer, its use as a pharmaceutical has been widely studied.Melatonin can be provided in either solid or liquid dosage forms.Liquid dosage forms are preferred for consumers who have difficulty swallowing pills or tablets, such as children or individuals who suffer from swallowing disorders.

[0009] Unfortunately, liquid dosage forms have a shorter shelf life than solid dosage forms.To overcome this drawback, excipients such as preservatives and / or antioxidants are often added to liquid formulations to extend their shelf life.Typically, these excipients are used in combination to achieve a satisfactory preservation effect.However, many excipients pose health risks to consumers, and therefore, the restriction of unnecessary excipients is advantageous.

[0010] Many examples of adverse effects of excipients have been documented. Parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben are suspected of causing allergies, endocrine disruption, and cancer. This has led to parabens being banned in some products, especially those intended for children. Benzoates such as sodium benzoate have been shown to cause hypersensitivity in individuals suffering from asthma and have also been linked to hyperactivity in children. Citric acid (E330), an antioxidant frequently used in connection with kidney disease, can cause mouth irritation or stomach upset for some people. Therefore, it is preferable to avoid liquid dosage forms without an excessive number of excipients, if possible.

[0011] Therefore, it would be advantageous to provide a liquid melatonin formulation that is free of unnecessary excipients and potentially harmful substances. In particular, an aqueous melatonin composition that contains only a single preservative would be advantageous for use in vulnerable individuals, such as children and adolescents. Summary of the Invention

[0012] Formulations for reducing sleep disorders are very important in terms of how many lives are affected every day. The naturally occurring neurohormone melatonin can be used to induce sleep without the severe risk of adverse effects associated with traditional synthetic hypnotic drugs. Unfortunately, in many cases, liquid formulations of melatonin contain unhealthy excipients such as excess preservatives or allergens. Thus, there is an unmet need to provide liquid melatonin compositions that are free of unnecessary and harmful substances.

[0013] The present invention is directed to the provision of a liquid melatonin formulation that contains a minimum of components. In particular, it has been found that storage stability can be maintained by the inclusion of a single, non-toxic preservative.

[0014] It is therefore an object of the present invention to provide a liquid melatonin formulation suitable for use in children, adolescents and individuals who react adversely to one or more excipients contained in similar products.

[0015] Accordingly, an aspect of the present invention is an aqueous melatonin composition comprising, dissolved in an aqueous phase: i) an active ingredient selected from melatonin; ii) a preservative selected from potassium sorbate; Including, the aqueous phase comprises at least about 85% w / v water; The composition relates to an aqueous melatonin composition that does not contain any added preservatives.

[0016] Another aspect of the present invention relates to an aqueous melatonin composition as described herein for use as a medicament.

[0017] Yet another aspect of the present invention relates to an aqueous melatonin composition as described herein for use in treating a sleep disorder.

[0018] A further aspect of the invention relates to a method for preparing the aqueous melatonin compositions described herein, the method comprising: i) providing an aqueous solvent; ii) adding potassium sorbate and melatonin to the aqueous solvent to obtain an aqueous melatonin solution; iii) adjusting the pH of the aqueous melatonin solution; iv) filtering the aqueous melatonin solution, Thereby, the aqueous melatonin composition is obtained.

[0019] Yet a further aspect of the present invention relates to aqueous melatonin compositions as described herein, obtainable by the methods described herein.

[0020] The invention is explained in more detail below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] definition Before outlining the invention in more detail, a set of terms and conventions are first defined.

[0022] Melatonin In this context, the term "melatonin" refers to a neurohormone released by the pineal gland in the brain. Melatonin has the chemical identity N-acetyl-5-methoxytrypamine. One form of melatonin is micronized melatonin, where the melatonin particles have been milled to reduce particle size.

[0023] Micronized Melatonin In the present context, the term "micronized melatonin" refers to a population of melatonin particles having a D90 of 30 μm or less as measured using laser diffraction. D90 represents the value at which 90% of the particles in a population have a diameter less than this value.

[0024] Particle size and particle size distribution (PSD) can be determined using a Malvern Mastersizer 2000 from Malvern Instruments equipped with a measuring cell Hydro 2000μP. This particle size analyzer is based on laser diffraction and can accurately determine the PSD of solid particulate melatonin. Low angle laser light scattering responds to the volume of the particles, yielding a volume average particle size, which corresponds to the weight average particle size if the density is held constant.

[0025] The settings on the Malvern Mastersizer 2000 (Hydro 2000S measuring cell) were as follows: [Table 1]

[0026] Preservatives In the present context, the term "preservative" refers to a substance or chemical that prevents the degradation of the aqueous melatonin composition by microbial growth or undesirable chemical changes.

[0027] One group of preservatives are antimicrobial preservatives that specifically prevent bacterial degradation. Antimicrobial preservatives include, but are not limited to, benzoates, parabens, sorbates, and isothiazolinones.

[0028] Antioxidants In the present context, the term "antioxidant" refers to a substance or chemical that prevents or inhibits the oxidation process. Antioxidants also include sequestering agents, such as citric acid, that scavenge metal ions that would otherwise catalyze the oxidation process.

[0029] active ingredient In the present context, the term "active ingredient" refers to any ingredient in a composition that is biologically or pharmacologically active. The term "active ingredient" encompasses both the "active pharmaceutical ingredient (API)" typically used in pharmaceuticals, and the "active substance" sometimes used in natural products.

[0030] The non-active ingredients are referred to herein as excipients.

[0031] alcohol In the present context, the term "alcohol" refers to any organic compound that contains one or more hydroxyl (OH) functional groups attached to a saturated carbon atom.

[0032] Alcohols include, but are not limited to, organic compounds having only a single hydroxyl group (monohydric alcohols), organic compounds having multiple hydroxyl groups (polyhydric alcohols), and cyclic alcohols.

[0033] Flavoring Agent In the present context, the term "flavoring agent" refers to a substance used to mask any unpleasant taste caused by the active ingredient or other ingredients and to improve the sensory experience of the consumer. Flavoring agents may be of natural or artificial origin.

[0034] Storage stability In the present context, the term "storage stability" refers to the properties of the product as defined by the European Pharmacopoeia 10 th In accordance with Ph.Eur.5.1.3 Efficacy of antimicrobial preservation (Ph.Eur.5.1.3), this refers to the minimum period for which a solution can be stored without spoilage due to microbial contamination.

[0035] Stability is assessed by challenging a solution such as the compositions described herein with a defined set of microorganisms and measuring the growth of the microorganisms over a four week period.

[0036] Storage stability over longer storage periods can be assessed by storing the composition and removing samples for the presence of microorganisms at various time points, such as after 3 months, 6 months, 1 year, and 2 years.

[0037] about Whenever the term "about" is used herein in the context of an amount, e.g., number, purity, weight, size, etc., absolute or relative amounts (e.g., percentages, equivalents, or ratios), time frames, and parameters such as temperature, pressure, etc., it will be understood that such variables are approximations and as such can vary from the actual number specified by ±10%, e.g., ±5%, preferably ±2% (e.g., ±1%). This is true even when such numbers are first presented as a percentage (e.g., "about 10%" can mean ±10% for the number 10, which is anywhere from 9% to 11%).

[0038] Solid dosage form melatonin formulations and methods for their manufacture Sleep disorders affect millions of individuals worldwide every day. Synthetic means to reduce the adverse effects of sleep disorders have existed for decades. Unfortunately, synthetic hypnotic agents, such as barbiturates, benzodiazepines, and benzodiazepine-like compounds, have questionable safety profiles and not all compounds have been shown to be effective.

[0039] Melatonin is a naturally occurring neurohormone that is an alternative active ingredient to combat sleep disorders that does not cause the severe adverse effects associated with its synthetic counterpart. However, many melatonin compositions are provided as liquid solutions that contain extensive preservatives that have been proven to cause significant short-term and long-term adverse effects, such as endocrine disruption, allergies, or eczema. In particular, a combination of excipients is utilized to obtain a long shelf life, with the obvious drawback that an increase in the number of compounds in the formulation increases the risk of adverse effects. Thus, there is an unmet need to provide melatonin as a health-friendly composition without any unnecessary excipients.

[0040] Provided herein is an aqueous melatonin composition containing only a single preservative, i.e., potassium sorbate. It has been found that a good preservative effect can be achieved by using potassium sorbate alone, as tested according to Ph.Eur.5.1.3. Furthermore, it has been found that potassium sorbate exhibits favorable organoleptic properties. The composition is safe and can be stored for long periods of time.

[0041] Accordingly, an aspect of the present invention is an aqueous melatonin composition comprising, dissolved in an aqueous phase: i) an active ingredient selected from melatonin; ii) a preservative selected from potassium sorbate; Including, the aqueous phase comprises at least 85% w / v water; The composition relates to an aqueous melatonin composition that does not contain any added preservatives.

[0042] The active ingredient, melatonin, may preferably be provided in micronized form. Micronized form of melatonin differs from conventional melatonin in that it is processed into smaller size particles. This processing affects particle characteristics such as shape, size, and size distribution. Thus, micronized melatonin particles are typically smaller than about 30 μm. Micronized form of melatonin is preferred to reduce the time required to dissolve melatonin during preparation of aqueous composition. Melatonin is added under high speed and vigorous stirring, so it is desirable to make this step as efficient as possible.

[0043] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein the melatonin is in the form of micronized melatonin.

[0044] Another embodiment of the invention relates to an aqueous melatonin composition as described herein, wherein the size (D90) of the micronized melatonin ranges from about 5 μm to about 20 μm, such as from about 5 μm to about 10 μm.

[0045] A further embodiment of the present invention relates to an aqueous melatonin composition as described herein, wherein the micronized melatonin has a D90 value of about 30 μm or less, preferably about 20 μm or less, and more preferably about 10 μm or less.

[0046] The concentration of melatonin is selected so that the active ingredient can be administered in doses of suitable size to a variety of individuals, e.g., children, adolescents, and adults. The remaining components of the aqueous melatonin composition are generally inactive, i.e., they do not significantly contribute to the sleep-inducing effect.

[0047] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein the concentration of melatonin is in the range of about 0.5 mg / ml to about 2.0 mg / ml, such as about 0.75 mg / ml to about 1.5 mg / ml, such as about 0.9 mg / ml to about 1.1 mg / ml, preferably about 1 mg / ml.

[0048] Another embodiment of the present invention relates to the aqueous melatonin compositions described herein, which do not include additional active ingredients.

[0049] Further embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein the additional active ingredient is an active pharmaceutical ingredient (API).

[0050] The good preservative effect observed with potassium sorbate does not require unusually high concentrations of preservatives compared to commercially available liquid formulations of melatonin that contain potassium sorbate in combination with preservatives different from potassium sorbate or additional preservatives.

[0051] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions described herein, wherein the concentration of potassium sorbate is less than about 2.0 mg / ml, such as less than about 1.5 mg / ml, such as less than about 1.2 mg / ml.

[0052] Another embodiment of the invention relates to an aqueous melatonin composition as described herein, wherein the concentration of potassium sorbate is in the range of about 0.5 mg / ml to about 2.0 mg / ml, such as about 0.75 mg / ml to about 1.5 mg / ml, such as about 0.9 mg / ml to about 1.1 mg / ml, preferably about 1 mg / ml.

[0053] Further embodiments of the present invention relate to aqueous melatonin compositions as described herein, comprising: i) about 0.5 mg / ml to about 2.0 mg / ml of melatonin, preferably about 1 mg / ml of melatonin; ii) about 0.5 mg / ml to about 2.0 mg / ml of potassium sorbate, preferably about 1 mg / ml of potassium sorbate.

[0054] Aqueous melatonin compositions may also include a solvent enhancer such as glycerol. Glycerol is essentially odorless, colorless, and hygroscopic due to the presence of three hydroxyl groups. Additionally, glycerol adds a sweet taste to liquid solutions.

[0055] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein the aqueous phase comprises glycerol.

[0056] Another embodiment of the invention relates to an aqueous melatonin composition as described herein, wherein the concentration of glycerol is in the range of about 70 mg / ml to 100 mg / ml, such as about 75 mg / ml to about 95 mg / ml, such as about 80 mg / ml to about 90 mg / ml, such as about 82 mg / ml to about 88 mg / ml, preferably about 85 mg / ml.

[0057] Further embodiments of the present invention relate to aqueous melatonin compositions as described herein, comprising: i) about 0.5 mg / ml to about 2.0 mg / ml of melatonin, preferably about 1 mg / ml of melatonin; ii) about 0.5 mg / ml to about 2.0 mg / ml potassium sorbate, preferably about 1 mg / ml potassium sorbate; iii) about 70 mg / ml to about 100 mg / ml glycerol, preferably about 85 mg / ml glycerol.

[0058] In order to optimize the stability of the aqueous melatonin composition, it is preferred to adjust the pH of the composition.Without being bound by theory, it is contemplated that too high a pH value may destabilize melatonin due to deprotonation of the amide functional group of the indole group in the melatonin structure.Therefore, a slightly acidic pH value is preferred.The adjustment of pH can be carried out with any suitable acid, such as HCl, that does not interfere with the properties of the aqueous melatonin composition.

[0059] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, the pH of which is in the range of about pH 3.5 to about pH 5.5, such as about pH 4.0 to about pH 5.0, such as about pH 4.2 to about pH 4.8, such as about pH 4.4 to about pH 4.6, preferably about pH 4.5.

[0060] As described herein, the aqueous melatonin compositions do not require additional preservatives beyond potassium sorbate, and in particular, it is preferable to avoid some of the traditional preservatives that can cause adverse effects upon ingestion.

[0061] Accordingly, an embodiment of the present invention relates to an aqueous melatonin composition, wherein the additional preservative is selected from the group consisting of parabens, benzoates, isothiazolinones, and antioxidants.

[0062] Another embodiment of the invention relates to an aqueous melatonin composition, wherein the additional preservative is selected from the group consisting of parabens, benzoates, isothiazolinones, antioxidants, and simple alcohols.

[0063] In the present context, the term "simple alcohol" refers to primary monoalcohols (RCH2OH), secondary monoalcohols (R2CHOH), and tertiary monoalcohols (R3COH).

[0064] It should be understood that glycerol in this context is not considered an added preservative. Instead, glycerol may be added to the composition as a solvent enhancer / thickener.

[0065] Thus, an embodiment of the present invention relates to an aqueous melatonin composition, wherein the additional preservative does not include glycerol.

[0066] Another embodiment of the invention relates to the aqueous melatonin compositions described herein, wherein the additional preservative is selected from the group consisting of parabens, sodium benzoate, benzyl alcohol, chlorobutanol, chlorocresol, alkyl esters of parabens, phenol, phenylethanol, propylene glycol, chloroform, benzoic acid, and antioxidants.

[0067] It is also preferable to avoid including antioxidants in aqueous melatonin compositions. For example, citric acid has been associated with side effects including muscle spasms or cramps, swelling or weight gain, weakness, mood changes, rapid and shallow breathing, fast heart rate, restlessness, or diarrhea. Therefore, individuals suffering from kidney problems, heart problems or elevated blood pressure, adrenal disorders, or hyperkalemia are not recommended to take extra citric acid. Furthermore, it is well established that liquids containing citric acid cause irreversible dental erosion (enamel erosion). Citric acid, especially synthetic citric acid, is also considered to have a strong negative impact on both individual and environmental health by a group of positive effects.

[0068] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, which do not contain an antioxidant.

[0069] Another embodiment of the invention relates to an aqueous melatonin composition as described herein, wherein the antioxidant is selected from the group consisting of citric acid, lecithin, vitamin C, vitamin E, flavonoids, anthocyanins, genistein, and quercetin.

[0070] A further embodiment of the present invention relates to the aqueous melatonin compositions described herein, wherein the antioxidant is citric acid.

[0071] Yet further embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein the antioxidant is lecithin.

[0072] Yet further embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein the antioxidant is citric acid and / or lecithin.

[0073] The intention of the melatonin composition described herein is to provide it as a composition as mild as possible for the benefit of consumers. Liquid compositions are easy to administer to individuals who are reluctant to swallow any solid dosage form, such as pills, and can be easily taken orally. Therefore, the composition is prepared as an aqueous composition, containing mainly water and very limited amounts of any other solvents. In particular, organic solvents, such as alcohol, are preferably avoided.

[0074] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, which are liquid compositions.

[0075] Another embodiment of the present invention relates to an aqueous melatonin composition as described herein, which is suitable for oral administration.

[0076] It should be understood that the melatonin of the composition is completely dissolved in the aqueous phase. The appearance of the composition is that of a solution, not a suspension, dispersion, etc. This means that the melatonin is neither in particulate form, such as in micro- or nanoparticle form, nor in an aggregated system, such as a lipid system. Thus, an undesirable aggregated system may be a liposomal or micelle system, including lipid compounds such as fatty acids and / or lecithin.

[0077] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, which are aqueous solutions.

[0078] Another embodiment of the present invention relates to an aqueous melatonin composition as described herein, which does not include melatonin in a particulate form, such as in nanoparticulate form.

[0079] Generally, it is undesirable for pharmaceutical products for human consumption to contain organic solvents such as alcohol. This is particularly true for products intended for consumption by children and / or adolescents.

[0080] Thus, a further embodiment of the present invention relates to an aqueous melatonin composition as described herein, which does not include any alcohol other than glycerol.

[0081] Another embodiment of the present invention relates to the aqueous melatonin compositions described herein, which do not include simple alcohol.

[0082] Yet another embodiment of the present invention relates to the aqueous melatonin compositions described herein, wherein the compositions do not include ethanol.

[0083] Yet further embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein the compositions do not include xylitol.

[0084] The aqueous phase of the composition contains both the active ingredient and the preservative. The aqueous phase preferably contains purified water to reduce the risk of any contaminants affecting the melatonin and its long-term stability and activity. In some variations of the aqueous melatonin composition, the water content (w / v) may be even higher than 85% w / v.

[0085] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein the aqueous phase comprises at least about 86% w / v water, such as about 87% w / v water, such as about 88% w / v water, such as about 89% w / v water, such as about 90% w / v water.

[0086] Another embodiment of the invention relates to the aqueous melatonin compositions described herein, wherein the water is purified water.

[0087] In a variation of the aqueous melatonin composition, the aqueous phase is not supplemented with a thickening agent, but viscoelastic properties are optionally permitted with the addition of glycerol.

[0088] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, which do not include any thickening agents.

[0089] Another embodiment of the present invention relates to an aqueous melatonin composition as described herein, which does not include any thickening agent other than glycerol.

[0090] A further embodiment of the present invention relates to an aqueous melatonin composition as described herein, which does not include any polymeric thickening agent.

[0091] Polymeric thickening agents include, but are not limited to, various gums and starches. Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein the thickening agent is selected from the group consisting of xanthan gum, arginine, guar gum, locust bean gum, starch, carrageenan, and gelatin.

[0092] Yet another embodiment of the present invention relates to the aqueous melatonin compositions described herein, wherein the thickening agent is xanthan gum.

[0093] It may also be desirable to add one or more flavoring agents to the composition to improve the consumer's sensory experience. Such flavoring agents are added only in small amounts that do not alter the physical or pharmacokinetic properties of the aqueous melatonin composition. Flavoring agents can be either natural (e.g., extracted from fruits, berries, stems, or leaves) or synthetic (e.g., synthetic aroma chemicals).

[0094] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, which further comprise one or more flavoring agents.

[0095] Another embodiment of the invention relates to the aqueous melatonin compositions described herein, wherein the flavoring agent has a flavor selected from the group consisting of strawberry, mint, banana, apple, coconut, cherry, lemon, vanilla, pineapple, orange, and combinations thereof.

[0096] Further embodiments of the present invention relate to the aqueous melatonin compositions described herein, wherein the one or more flavoring agents are selected from the group consisting of maltol, vanillin, ethyl vanillin, menthol, malic acid, fumaric acid, ethyl maltol, tartaric acid, isoamyl acetate, gamma-octalactone, allyl hexanoate, ethyl butyrate, cinnamaldehyde, ethyl 2-methylpentanoate, methylphenylglycidate, and combinations thereof.

[0097] Certain aqueous melatonin compositions have been identified as being preferred and as having good stability during storage and / or when challenged with microorganisms.

[0098] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, which compositions comprise: i) melatonin, ii) potassium sorbate; iii) an aqueous solvent containing purified water and glycerol;

[0099] Another embodiment of the present invention relates to an aqueous melatonin composition as described herein, comprising: i) melatonin, ii) potassium sorbate; iii) glycerol; iv) hydrochloric acid; v) purified water.

[0100] Further embodiments of the present invention relate to aqueous melatonin compositions as described herein, comprising: i) about 1 mg / ml of melatonin; ii) about 1 mg / ml potassium sorbate; iii) about 85 mg / ml glycerol; iv) hydrochloric acid; v) purified water.

[0101] Yet further embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein the pH of the composition is about pH 4.5.

[0102] Pharmaceutical compositions require some antimicrobial activity to prevent risk to the consumer from infection and spoilage of the composition due to microbial growth during storage. This is particularly problematic with aqueous formulations. For this purpose, compounds with antimicrobial activity are added. For the aqueous melatonin compositions described herein, the compound with antimicrobial activity is potassium sorbate. The storage stability of aqueous melatonin compositions is evaluated according to the European Pharmacopoeia 10 th The efficacy of the antimicrobial agent may be determined by measuring the antimicrobial activity in accordance with the International Standards Board for Food and Drug Administration (IAS 81 / 100 / EC), 5.1.3 Efficacy of antimicrobial preservation (Ph.Eur.5.1.3).

[0103] It should therefore be understood that storage stability in this context relates to antimicrobial stability and does not therefore refer, for example, to the stabilization of the components of the composition or the ability to keep (nano)particles in suspension.

[0104] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein storage stability is assessed according to Ph.Eur.5.1.3 (10th edition).

[0105] Another embodiment of the invention relates to an aqueous melatonin composition according to any one of the preceding paragraphs, wherein the storage stability of the composition is in accordance with the European Pharmacopoeia 10 th for at least 4 weeks, as determined by measurement of antimicrobial activity in accordance with International Standards Board, Edition, 5.1.3 Efficacy of antimicrobial preservation (Ph.Eur.5.1.3).

[0106] Further embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein the compositions are stable upon storage at room temperature for at least 12 months, such as at least 18 months, such as at least 24 months.

[0107] Yet further embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein the compositions have a storage stability at room temperature of at least 12 months, such as at least 18 months, such as at least 24 months.

[0108] The aqueous melatonin composition is a neurohormone known to play an active role in circadian rhythm, particularly influencing sleep-wake timing.Thus, it finds medical use for those individuals with irregular sleep patterns.As described herein, melatonin is preferred over traditional hypnotic agents because it has limited risk of adverse effects and dependency.

[0109] Accordingly, an aspect of the present invention relates to an aqueous melatonin composition as described herein for use as a medicament.

[0110] Another aspect of the invention relates to an aqueous melatonin composition as described herein for use in treating a sleep disorder.

[0111] The aqueous melatonin compositions described herein are useful for treating sleep disorders, such as insomnia. There are many variations of insomnia, including but not limited to sleep maintenance insomnia, sleep termination insomnia, sleep onset insomnia, and psychophysiological insomnia. However, the aqueous melatonin compositions can also be used to treat disorders related to circadian rhythm, including but not limited to jet lag, shift work sleep disorder, delayed sleep phase disorder (DSPS), and non-24-hour sleep-wake disorder.

[0112] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein the sleep disorder is selected from the group consisting of insomnia, circadian rhythm-associated sleep disorder, delayed sleep phase disorder (DSPS), jet lag, sleep disorder associated with a psychiatric condition, sleep disorder associated with a neurological disease, sleep disorder associated with a mental condition, and sleep disorder associated with a medical disorder.

[0113] Another embodiment of the present invention relates to an aqueous melatonin composition as described herein, wherein the sleep disorder is a circadian rhythm-related sleep disorder.

[0114] Another patient group that can benefit from the aqueous melatonin compositions described herein are those who experience sleep disorders resulting from psychiatric conditions and / or neurological diseases. These patients may suffer from attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), dementia, or parkinsonism. Sleep disorders also often occur in combination with psychiatric disorders, such as psychosis or mood and anxiety disorders, or in conjunction with medical disorders, such as chronic obstructive pulmonary disease and nocturnal cardiac ischemia.

[0115] An embodiment of the present invention relates to an aqueous melatonin composition for use as described herein, wherein the sleep disorder is insomnia due to ADHD.

[0116] Another embodiment of the present invention relates to an aqueous melatonin composition for uses as described herein, wherein the immediate release melatonin formulation is administered to an individual who has discontinued use of a benzodiazepine or non-benzodiazepine hypnotic drug.

[0117] A further embodiment of the present invention relates to an aqueous melatonin composition for uses as described herein, wherein the sleep disorder is insomnia.

[0118] The aqueous melatonin composition is formulated so that it can be conveniently administered by ingestion via the mouth. The recommended dosage may vary depending on the subject being treated.

[0119] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein the compositions are administered to a subject via the oral route.

[0120] Another embodiment of the invention relates to an aqueous melatonin composition as described herein, wherein the composition is administered in a dose comprising 0.5 to 20 mg of melatonin, such as 0.75 to 10 mg of melatonin, such as 1 to 5 mg of melatonin.

[0121] The subject to be treated may in principle be any mammal, and there may be circumstances in which animals, such as pet animals, may benefit from administration of the aqueous melatonin compositions. However, the subject is preferably a human. In particular, children, adolescents, and the elderly, who may be more vulnerable to the side effects of excessive and potentially harmful excipients, may benefit from the aqueous melatonin compositions described herein.

[0122] Accordingly, embodiments of the present invention relate to aqueous melatonin compositions as described herein, in which the subject is a human.

[0123] Another embodiment of the invention relates to an aqueous melatonin composition as described herein, wherein the subject is a child or adolescent.

[0124] Further embodiments of the present invention relate to aqueous melatonin compositions as described herein, wherein the compositions are administered to children or adolescents with ADHD or a neuropsychiatric disorder.

[0125] Yet further embodiments of the present invention relate to aqueous melatonin compositions for uses as described herein, wherein the composition is administered to adults 50 years of age or older, such as 55 years of age or older, such as 60 years of age or older, such as 70 years of age or older, such as 80 years of age or older.

[0126] Aqueous melatonin compositions can be prepared on an industrial scale by carefully mixing melatonin and potassium sorbate in the aqueous phase, followed by pH adjustment and purification.

[0127] Accordingly, aspects of the present invention relate to aqueous melatonin compositions as described herein, obtainable by the methods described herein.

[0128] Another aspect of the invention relates to a method for preparing the aqueous melatonin compositions described herein, the method comprising: i) providing an aqueous phase; ii) adding potassium sorbate and melatonin to the aqueous phase to obtain an aqueous melatonin solution; iii) adjusting the pH of the aqueous melatonin solution; iv) filtering the aqueous melatonin solution, Thereby, the aqueous melatonin composition is obtained.

[0129] An embodiment of the present invention relates to the methods described herein, wherein the aqueous phase comprises purified water.

[0130] Glycerol may be added to the aqueous phase of the composition as a solvent enhancer. Accordingly, an embodiment of the present invention relates to a method as described herein, wherein the aqueous phase comprises glycerol.

[0131] It has been found that dispersion of the components of the composition can be effectively achieved by continuous stirring, for example with a magnetic stirrer, a propeller, preferably a propeller. The stirring speed can be selected to reduce production time and to efficiently dissolve the components without splashing or foaming.

[0132] Thus, an embodiment of the present invention relates to the method described herein, wherein the addition of potassium sorbate and melatonin is carried out under continuous stirring.

[0133] Another embodiment of the present invention relates to a method as described herein, wherein the stirring is performed in three successive steps, a first at about 575 rpm, a second at about 350 rpm, and a third at about 200 rpm.

[0134] The pH of the aqueous melatonin composition may be adjusted by any suitable acid that does not inadvertently alter the properties of the composition. The acid may be HCl. The acid may be conveniently titrated into the composition until the desired pH is achieved.

[0135] Accordingly, an embodiment of the present invention relates to the methods described herein, wherein the adjustment of the pH is performed using hydrochloric acid (HCl).

[0136] Another embodiment of the present invention relates to the methods described herein, wherein the pH is adjusted to a range of about 4.4 to about 4.6, preferably to a pH of about 4.5.

[0137] The aqueous melatonin composition is filtered to remove any particulate matter. Filtration of the solution can be accomplished by passing the composition through a membrane filter of defined pore size.

[0138] Accordingly, embodiments of the present invention relate to methods as described herein, wherein filtration is performed with a membrane filter having a pore size in the range of about 0.5 μm to about 1.5 μm, such as about 0.8 μm to about 1.2 μm, preferably about 1.0 μm.

[0139] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0140] Preferences, options, and embodiments of any given aspect, feature, or parameter of the invention should be considered as disclosed in combination with any and all preferences, options, and embodiments of all other aspects, features, and parameters of the invention, unless the context dictates otherwise. This is particularly true for the description of aqueous melatonin compositions and all features that may readily be part of the methods described herein.

[0141] Embodiments and features of the present invention are also outlined in the following sections.

[0142] item X1. An aqueous melatonin composition, comprising: i) an active ingredient selected from melatonin; ii) a preservative selected from potassium sorbate; Including, the aqueous phase comprises at least about 85% w / v water; An aqueous melatonin composition, wherein the composition does not contain any added preservatives.

[0143] X2. The aqueous melatonin composition of paragraph X1, wherein the melatonin is in the form of micronized melatonin.

[0144] X3. The aqueous melatonin composition of any one of paragraphs X1 or X2, wherein the size (D90) of the micronized melatonin is in the range of about 5 μm to about 20 μm, such as about 5 μm to about 10 μm.

[0145] X4. The aqueous melatonin composition of any one of the preceding items, wherein the concentration of melatonin is in the range of about 0.5 mg / ml to about 2.0 mg / ml, such as about 0.75 mg / ml to about 1.5 mg / ml, such as about 0.9 mg / ml to about 1.1 mg / ml, preferably about 1 mg / ml.

[0146] X5. The aqueous melatonin composition of any one of the preceding items, wherein the composition does not contain an additional active ingredient.

[0147] X6. The aqueous melatonin composition of any one of the preceding items, wherein the concentration of potassium sorbate is less than about 2.0 mg / ml, such as less than about 1.5 mg / ml, such as less than about 1.2 mg / ml.

[0148] X7. The aqueous melatonin composition of any one of the preceding items, wherein the concentration of potassium sorbate is in the range of about 0.5 mg / ml to about 2.0 mg / ml, such as about 0.75 mg / ml to about 1.5 mg / ml, such as about 0.9 mg / ml to about 1.1 mg / ml, preferably about 1 mg / ml.

[0149] X8. The composition, i) about 0.5 mg / ml to about 2.0 mg / ml of melatonin, preferably about 1 mg / ml of melatonin; ii) about 0.5 mg / ml to about 2.0 mg / ml of potassium sorbate, preferably about 1 mg / ml of potassium sorbate.

[0150] X9. The aqueous melatonin composition of any one of the preceding items, wherein the aqueous phase comprises glycerol.

[0151] X10. The aqueous melatonin composition according to item X9, wherein the concentration of glycerol is in the range of about 70 mg / ml to 100 mg / ml, such as about 75 mg / ml to about 95 mg / ml, such as about 80 mg / ml to about 90 mg / ml, such as about 82 mg / ml to about 88 mg / ml, preferably about 85 mg / ml.

[0152] X11. The composition, i) about 0.5 mg / ml to about 2.0 mg / ml of melatonin, preferably about 1 mg / ml of melatonin; ii) about 0.5 mg / ml to about 2.0 mg / ml potassium sorbate, preferably about 1 mg / ml potassium sorbate; iii) about 70 mg / ml to about 100 mg / ml glycerol, preferably about 85 mg / ml glycerol.

[0153] X12. The aqueous melatonin composition of any one of the preceding paragraphs, wherein the pH of the composition is in the range of about pH 3.5 to about pH 5.5, such as about pH 4.0 to about pH 5.0, such as about pH 4.2 to about pH 4.8, such as about pH 4.4 to about pH 4.6, preferably about pH 4.5.

[0154] X13. The aqueous melatonin composition of any one of the preceding items, wherein the additional preservative is selected from the group consisting of parabens, sodium benzoate, benzyl alcohol, chlorobutanol, chlorocresol, alkyl esters of parabens, phenol, phenylethanol, propylene glycol, chloroform, benzoic acid, and antioxidants.

[0155] X14. The aqueous melatonin composition of any one of the preceding items, wherein the composition does not contain an antioxidant.

[0156] X15. The aqueous melatonin composition of any one of paragraphs X13 or X14, wherein the antioxidant is selected from the group consisting of citric acid, lecithin, vitamin C, vitamin E, flavonoids, anthocyanins, genistein, and quercetin.

[0157] X16. The aqueous melatonin composition according to any one of paragraphs X13-X15, wherein the antioxidant is citric acid.

[0158] X17. The aqueous melatonin composition of any one of the preceding items, wherein the composition does not contain any alcohol other than glycerol.

[0159] X18. The aqueous melatonin composition of any one of the preceding items, wherein the composition does not contain xylitol.

[0160] X19. The aqueous melatonin composition of any one of the preceding items, wherein the composition does not contain any thickening agents.

[0161] X20. The aqueous melatonin composition of item X19, wherein the thickening agent is selected from the group consisting of xanthan gum, arginine, guar gum, locust bean gum, starch, carrageenan, and gelatin.

[0162] X21. The aqueous melatonin composition of any one of items X19 or X20, wherein the thickening agent is xanthan gum.

[0163] X22. The aqueous melatonin composition of any one of the preceding items, wherein the composition is a liquid composition.

[0164] X23. The aqueous melatonin composition of any one of the preceding items, wherein the composition is suitable for oral administration.

[0165] X24. The aqueous melatonin composition of any one of the preceding items, wherein the aqueous phase comprises at least about 86% w / v water, such as about 87% w / v water, such as about 88% w / v water, such as about 89% w / v water, such as about 90% w / v water.

[0166] X25. The aqueous melatonin composition of any one of the preceding items, wherein the water is purified water.

[0167] X26. The aqueous melatonin composition of any one of the preceding items, wherein the composition further comprises one or more flavoring agents.

[0168] X27. The aqueous melatonin composition of item X26, wherein the flavoring agent has a flavor selected from the group consisting of strawberry, mint, banana, apple, coconut, cherry, lemon, vanilla, pineapple, orange, and combinations thereof.

[0169] X28. The composition, i) melatonin, ii) potassium sorbate; iii) an aqueous solvent comprising purified water and glycerol;

[0170] X29. The composition, i) melatonin, ii) potassium sorbate; iii) glycerol; iv) hydrochloric acid; v) purified water.

[0171] X30. The composition, i) about 1 mg / ml of melatonin; ii) about 1 mg / ml potassium sorbate; iii) about 85 mg / ml glycerol; iv) hydrochloric acid; v) purified water.

[0172] X31. The aqueous melatonin composition of any one of the preceding items, wherein the pH of the composition is about pH 4.5.

[0173] X32. The aqueous melatonin composition of any one of the preceding items, wherein the composition is stable upon storage at room temperature for at least 12 months, such as at least 18 months, such as at least 24 months.

[0174] X33. The aqueous melatonin composition according to item 32, wherein the storage stability is evaluated according to Ph.Eur.5.1.3 (10th edition).

[0175] Y1. An aqueous melatonin composition according to any one of the preceding items for use as a medicament.

[0176] Y2. The aqueous melatonin composition of any one of the preceding items for use in treating a sleep disorder.

[0177] Y3. The aqueous melatonin composition for use according to item Y2, wherein the sleep disorder is selected from the group consisting of insomnia, circadian rhythm associated sleep disorder, delayed sleep phase disorder (DSPS), jet lag, sleep disorder associated with a psychiatric condition, sleep disorder associated with a neurological disease, sleep disorder associated with a mental condition, sleep disorder associated with a medical disorder.

[0178] Y4. An aqueous melatonin composition for use according to any one of paragraphs Y1-Y3, wherein the composition is administered to the subject via the oral route.

[0179] Y5. The aqueous melatonin composition for use according to any one of paragraphs Y1-Y4, wherein the composition is administered in a dose comprising 0.5-20 mg of melatonin, such as 0.75-10 mg of melatonin, such as 1-5 mg of melatonin.

[0180] Y6. The aqueous melatonin composition for use according to any one of paragraphs Y1-Y5, wherein the subject is a human.

[0181] Y7. An aqueous melatonin composition for use according to any one of paragraphs Y1-Y6, wherein the subject is a child or an adolescent.

[0182] W1. A method for preparing an aqueous melatonin composition according to any one of paragraphs X1-X33, the method comprising: i) providing an aqueous phase; ii) adding potassium sorbate and melatonin to the aqueous phase to obtain an aqueous melatonin solution; iii) adjusting the pH of the aqueous melatonin solution; iv) filtering the aqueous melatonin solution, Thereby, the aqueous melatonin composition is obtained.

[0183] W2. The method of claim W1, wherein the aqueous phase comprises purified water.

[0184] W3. The method of any one of paragraphs W1 or W2, wherein the aqueous phase comprises glycerol.

[0185] W4. The method according to any one of items W1 to W3, wherein the addition of potassium sorbate and melatonin is carried out under continuous stirring.

[0186] W5. The method according to item W4, wherein the stirring is carried out in three successive steps, a first at about 575 rpm, a second at about 350 rpm, and a third at about 200 rpm.

[0187] W6. The method according to any one of items W1 to W5, wherein the adjustment of the pH is carried out using hydrochloric acid (HCl).

[0188] W7. The method according to any one of items W1 to W6, wherein the pH is adjusted to a range of about 4.4 to about 4.6, preferably to a pH of about 4.5.

[0189] W8. The method according to any one of items W1 to W7, wherein the filtration is carried out with a membrane filter having a pore size in the range of about 0.5 μm to about 1.5 μm, such as about 0.8 μm to about 1.2 μm, preferably about 1.0 μm.

[0190] Z1. An aqueous melatonin composition according to any one of items X1 to X33, obtainable by a method according to any one of items W1 to W8.

[0191] The invention will now be described in further detail in the following non-limiting examples. EXAMPLES

[0192] Example 1: Preparation of an aqueous melatonin composition This example describes how an exemplary version of an aqueous melatonin composition can be prepared. The exemplary composition follows Table 1. [Table 2]

[0193] The ingredients listed in Table 2 were used to prepare 80 liters of a 1 mg / mL melatonin solution with a final weight of 81.6 kg. [Table 3]

[0194] method The manufacturing process consists of three steps, with the final step being only necessary for storage and distribution. - Step 1: Preparation of oral solution -Step 2: Filtration -Step 3: Filling the bulk solution into the primary packaging

[0195] Step 1: Prepare the oral solution The oral solution was prepared using a 100 L stainless steel vessel.

[0196] The ingredients were dispensed and added to a stainless steel container in the following order: 1. Most of the purified water was placed in a mixing vessel and then the glycerol was added. The glycerol was dissolved by mixing with a propeller overhead stirrer. 2. Potassium sorbate and micronized melatonin were added to the glycerol in water solution and dissolved under continuous mixing using a propeller overhead stirrer at the highest speed possible without splashing (approximately 575 rpm). When nearly all solid components were dissolved, the mixing speed was reduced to reduce the amount of foam (approximately 350 rpm). Stirring was continued at a slower speed (approximately 200 rpm) until a clear solution without foam was obtained. Dissolution of melatonin and potassium sorbate was checked and verified by visual inspection. 3. The pH of the oral solution in the preparation vessel was measured and hydrochloric acid (2M) was slowly added to the solution under continuous mixing at low speed to achieve a target pH of 4.5 (measured with a Mettler Toledo Seven2Go). 4. The final weight of the formulation was adjusted by adding the remaining amount of purified water. Finally, the pH was verified to be 4.5.

[0197] Step 2: Filtration The completed oral solution was filtered to remove any particulate matter using a disposable membrane filter (Pall Nova Star, pore size 1.0 μm). The membrane filter was assembled with 8 mm inner diameter silicone tubing (Watson-Marlow, Flexicon Accusil) and the solution was pumped through the membrane filter using a peristaltic pump (Flexicon PF7) into a covered stainless steel container.

[0198] Step 3: Filling the package The filtered oral solution was filled into 100 mL amber glass bottles through 8 mm inner diameter silicone tubing (Watson-Marlow, Flexicon Accusil) using a Flexicon PF7 filling machine. The filled bottles were immediately sealed with polypropylene (PP) snap-on caps.

[0199] result The process produced a clear aqueous melatonin composition with all ingredients properly mixed and dissolved. The pH was controlled to obtain maximum stability of the composition.

[0200] conclusion A protocol was established to reliably and reproducibly produce aqueous melatonin compositions, which was utilized to prepare a variety of melatonin and placebo compositions and evaluate the characteristics of the aqueous melatonin compositions (Examples 2-4).

[0201] Example 2: Testing the sensory properties of aqueous compositions This example was designed to test how the components of an aqueous melatonin composition affect the sensory properties of the formulation. Appearance and odor were the sensory properties evaluated.

[0202] method The compositions were prepared according to the protocol described in Example 1, except that either potassium sorbate and / or methylparaben were added as preservative(s) according to Table 3. For placebo samples without melatonin, the addition of melatonin was omitted.

[0203] The batch sizes were smaller than in Example 1: 2000 mL (Sample A), 600 mL (Samples B and C), and 700 mL (Sample D). [Table 4]

[0204] Accelerated stability studies at 40°C / 75% RH were performed to investigate the sensory properties of the compositions over time. All studies were repeated in six replicates, i.e., storage of six separate bottles with samples A-D.

[0205] result The results of the composition appearance and odor development are presented in Table 4. The composition containing the active ingredient (Sample D) exhibited a deeper yellow color than the placebo compositions (Samples A-C). Omission of the second preservative did not cause a change in the color of the composition.

[0206] Importantly, the medicinal odor identified in the composition containing methylparaben was not present in the composition containing only potassium sorbate, therefore the odor was caused by methylparaben. [Table 5]

[0207] conclusion This example demonstrates that potassium sorbate does not cause an unpleasant odor to the composition and does not contribute negatively to the color of the composition.

[0208] Example 3: Testing the Microbial Stability of Aqueous Melatonin Compositions This example evaluates the effectiveness of antimicrobial preservation of an aqueous melatonin composition with different preservation means.

[0209] method The compositions were prepared according to the protocol described in Example 1, except that either potassium sorbate and / or methylparaben were added as preservative(s) according to Table 5. In the case of BN838, no preservatives were added. [Table 6]

[0210] A modified preservative efficacy test (PET) was performed using Aspergillus brasiliensis (ATCC 16404), Candida albicans (ATCC 10231), Escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 9027), and Staphylococcus aureus (ATCC 6538). The methodology was based on USP <51> and Ph.Eur.5.1.3 and the results were assessed against Ph.Eur.5.1.3 using the pass criteria set out therein.

[0211] Culture medium The following media were used: 0.9% NaCl, 0.9% NaCl + 0.05% Tween 80, Buffered NaCl Peptone (BNP) containing 1% Tween 80, Saboreau Dextrose Agar (SDA), and Tryptone Soy Agar (TSA).

[0212] microorganisms Frozen stock suspensions of microorganisms were used. The microorganisms were 5 passages or less from the original master seed lot. The microorganisms were thawed and mixed before use. The microorganisms were inoculated onto solid agar media. After incubation, the microorganisms were harvested in 0.9% NaCl (0.9% NaCl with 0.05% Tween 80 for A. brasiliensis) to give a suspension concentration of approximately 1 × 10 8 The concentration was adjusted to colony forming units (cfu) / mL. The culture medium and incubation time were in accordance with Ph Eur 5.1.3.

[0213] Methodological suitability / validity study evaluation A method suitability evaluation was performed and pre-approved to verify the suitability of the filtration method used in the study. 1 mL of sample BL716 was mixed with 100 mL of BNP containing 1% Tween 80. 10 mL was added in duplicate to a filtration funnel, inoculated with the test organism and then filtered. After rinsing the filters with 3 × 100 mL of 0.9% NaCl, they were placed on TSA or SDA plates and incubated. For reference, 10 mL of BNP containing 1% Tween 80 was inoculated and filtered in the same way. The recovery of the inoculum, i.e. the ratio between the growth in the inoculated product and the reference, should be between 50 and 200% for all microorganisms.

[0214] Testing the effectiveness of antibacterial preservation Separately in sterile containers, about 10 4 ~10 5 Antimicrobial preservative effectiveness tests were performed on 15 mL samples mixed with cfu / mL of each microorganism. As a reference, equal concentrations of all microorganisms, representing day 0, were added to one bottle each containing 20 mL of 0.9% NaCl. The references were serially diluted 10-fold and immediately tested in duplicate by the surface spread method.

[0215] The inoculated samples were incubated at 20-25°C for 28 days and tested on days 14 and 28. 1 mL of sample was mixed in 100 mL of BNP containing 1% Tween 80. Different volumes of the solution (0.1, 1, and 10 mL) were filtered, after which the filters were washed three times with 100 mL of 0.9% NaCl. The filters were then placed on tryptone soy agar (TSA) plates for bacteria and Saboreau dextrose agar (SDA) plates for fungi.

[0216] E. coli, P. aeruginosa, and S. aureus were incubated at 30-35° C. for more than 72 hours. C. albicans was incubated at 20-25° C. for more than 72 hours. A. brasiliensis was incubated at 20-25° C. for more than 120 hours. After incubation, the number of cfu on each plate was counted.

[0217] result Data from the validation study are presented in Table 6 and show that all microorganisms grew within the specified limits. [Table 7]

[0218] The results from the PET study are presented in Tables 7 and 8, and a comparison with the acceptance criteria set out in Ph Eur 5.1.3 is presented in Table 9. [Table 8] [Table 9] [Table 10]

[0219] All samples containing preservatives (BL716, BN836, and BN837) showed log densities of 100% or more for both bacteria and fungi as described in Ph.Eur.5.1.3. 10 The control sample (BN838) that did not contain preservatives did not meet the Ph.Eur.5.1.3 criteria.

[0220] In particular, the sample containing only potassium sorbate (1 mg / mL, BN837) performed overall well, as did the sample containing twice the amount of both potassium sorbate and methyl paraben (2 mg / mL, BL716), and was significantly better against fungi than the sample containing the same amounts of both potassium sorbate and methyl paraben (1 mg / mL, BN836).

[0221] conclusion This example demonstrates that efficient antimicrobial preservation of aqueous melatonin compositions can be achieved by using only potassium sorbate as the preservative.

[0222] Example 4: Testing the Limitations of Aqueous Melatonin Compositions This example investigated the limitations of potassium sorbate and pH of aqueous melatonin compositions via PET studies.

[0223] method The compositions were prepared according to the protocol described in Example 1. Three compositions were prepared according to Table 9. [Table 11]

[0224] The media, microorganisms, and methodology in this example were the same as in Example 3.

[0225] result The results from the PET study are presented in Tables 11 and 12, and a comparison with the acceptance criteria set out in Ph Eur 5.1.3 is presented in Table 13. [Table 12] [Table 13] [Table 14]

[0226] All samples were tested for both bacteria and fungi using the log 10 The reduction criteria were met. No significant differences were observed between samples containing 1 mg / ml (BS801) and 0.9 mg / ml (BS802) potassium sorbate. At pH 4.7, the preservative effect of potassium sorbate against fungi was reduced (BS803).

[0227] conclusion This example demonstrates that potassium sorbate provides effective antimicrobial preservation of aqueous melatonin compositions even when the concentration is slightly reduced or the pH is altered.

Claims

1. 1. An aqueous melatonin composition comprising: i) an active ingredient selected from melatonin; ii) a preservative selected from potassium sorbate; Including, the aqueous phase comprises at least about 85% w / v water; An aqueous melatonin composition, wherein the composition does not contain any added preservatives.

2. 2. The aqueous melatonin composition of claim 1, wherein the concentration of melatonin is in the range of about 0.5 mg / ml to about 2.0 mg / ml, such as about 0.75 mg / ml to about 1.5 mg / ml, such as about 0.9 mg / ml to about 1.1 mg / ml, preferably about 1 mg / ml.

3. 3. The aqueous melatonin composition of claim 1 or 2, wherein the composition does not contain any additional active ingredients.

4. 4. The aqueous melatonin composition of claim 1, wherein the concentration of potassium sorbate is in the range of about 0.5 mg / ml to about 2.0 mg / ml, such as about 0.75 mg / ml to about 1.5 mg / ml, such as about 0.9 mg / ml to about 1.1 mg / ml, preferably about 1 mg / ml.

5. 5. The aqueous melatonin composition of claim 1, wherein the aqueous phase comprises glycerol.

6. 6. The aqueous melatonin composition of any one of claims 1 to 5, wherein the additional preservatives are selected from the group consisting of parabens, sodium benzoate, benzyl alcohol, chlorobutanol, chlorocresol, alkyl esters of parabens, phenol, phenylethanol, propylene glycol, chloroform, benzoic acid, and antioxidants.

7. 7. The aqueous melatonin composition of any one of claims 1 to 6, wherein the composition does not contain any alcohol other than glycerol.

8. 8. The aqueous melatonin composition of any one of claims 1 to 7, wherein the composition does not contain any thickening agents.

9. 9. The aqueous melatonin composition of any one of claims 1 to 8, wherein the composition is stable upon storage at room temperature for at least 12 months, such as at least 18 months, such as at least 24 months.

10. 10. An aqueous melatonin composition according to any one of claims 1 to 9 for use as a medicament.

11. 11. An aqueous melatonin composition according to any one of claims 1 to 10 for use in the treatment of a sleep disorder.

12. 12. The aqueous melatonin composition for use according to claim 11, wherein the sleep disorder is selected from the group consisting of insomnia, circadian rhythm associated sleep disorder, delayed sleep phase disorder (DSPS), jet lag, sleep disorder associated with a psychiatric condition, sleep disorder associated with a neurological disease, sleep disorder associated with a mental condition, sleep disorder associated with a medical disorder.

13. 13. The aqueous melatonin composition for use according to any one of claims 10 to 12, wherein the composition is administered to a subject selected from a child or an adolescent.

14. 10. A method for preparing an aqueous melatonin composition according to any one of claims 1 to 9, said method comprising: i) providing an aqueous phase; ii) adding potassium sorbate and melatonin to the aqueous phase to obtain an aqueous melatonin solution; iii) adjusting the pH of the aqueous melatonin solution; iv) filtering the aqueous melatonin solution; Thereby, the aqueous melatonin composition is obtained.

15. 15. An aqueous melatonin composition according to any one of claims 1 to 9, obtainable by a method according to claim 14.

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