Melatonin liquid preparation

Abstract

The present invention provides an oily vehicle-based liquid formulation of melatonin, its method of manufacture, and its use in medicine, more particularly in the treatment of sleep disorders such as insomnia and circadian rhythm sleep-wake disorders.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to liquid formulations of melatonin, particularly suspensions, their preparation, and their use in medicine, particularly in the treatment of sleep disorders such as insomnia and circadian rhythm sleep-wake disorders.

[0002] Melatonin is a hormone secreted primarily by the pineal gland at night. In vertebrates, it is involved in the synchronization of circadian rhythms, including sleep-wake timing and blood pressure regulation, and the control of seasonal rhythms, including reproduction, fattening, molting, and hibernation.

[0003] Melatonin is used as a dietary supplement or pharmaceutical in the treatment of sleep disorders such as insomnia and circadian rhythm sleep-wake disorders.

[0004] Melatonin is approved as a medicine in the European Union for use in the short-term treatment of various types of insomnia and jet lag, and is administered in immediate-release and extended-release tablet form.

[0005] Melatonin is also available as a dietary supplement in many countries for sleep disorders. It can be administered orally (capsules, tablets, gummies, liquid), sublingually (spray or tablets), or as a transdermal patch.

[0006] Melatonin is widely available as an oral solid dosage form, but a liquid formulation is needed, especially for children under the age of three (infants), as patients in this age group often have difficulty swallowing solid tablets or dietary supplements, making a liquid formulation easier to ingest.

[0007] Liquid formulations of melatonin should not only be technically feasible, but also physicochemically stable, microbiologically acceptable, and ideally have good organoleptic properties.

[0008] Melatonin is typically available as an oral liquid formulation, typically based on an aqueous solvent alone or primarily on an aqueous solvent. However, due to stability issues and poor sensory properties, these liquid formulations usually contain preservatives (e.g., ethyl alcohol, sodium benzoate, potassium sorbate), thickeners (glycerin), and other excipients (sweeteners). Furthermore, these excipients are generally not suitable for administration to infants under the age of 3.

[0009] Therefore, there remains a need in the art for a formulation comprising melatonin in a liquid form that exhibits physical, chemical, and microbiological stability, good organoleptic properties, and is acceptable for use in children under the age of three, which provides additional benefits to healthcare professionals and patients compared to currently available formulations. Summary of the Invention

[0010] The present inventors have surprisingly found that the selection of oily vehicle and viscosity-increasing agent results in an oral liquid formulation, preferably a suspension, of melatonin that is physically, chemically and microbiologically stable under non-refrigerated conditions for at least six months, and that is palatable, thereby improving patient and caregiver acceptance.

[0011] Specifically, the formulation exhibits a decrease in melatonin concentration of at most 10%, preferably at most 7%, more preferably at most 5%, even more preferably at most 3%, and even more preferably at most 1% after 6 months of storage compared to the melatonin concentration observed at the start of storage. More specifically, the storage can be carried out under conditions of 25°C / 60% relative humidity (RH) and / or 40°C / 75% RH.

[0012] Furthermore, the formulations of the present invention maintain their appearance and organoleptic properties when stored under the above conditions for at least six months.

[0013] Furthermore, the suspensions of the present invention have low settling and can be easily reconstituted into a uniform suspension with gentle agitation as needed, eliminating variations in melatonin concentration throughout the vehicle and ensuring uniformity of dosage.

[0014] The inventors have further discovered that the addition of preservatives is not necessary to prevent microbial contamination of the liquid formulations of the present invention.

[0015] Furthermore, it has been surprisingly found that in order to obtain the physicochemically stable liquid formulation of melatonin of the present invention, it is not necessary to add any excipients other than the oily vehicle and the viscosity-increasing agent.

[0016] This formulation can be used in patients of all ages but is particularly suitable for pediatric use. It is a liquid, a preferred dosage form for young children, and contains the recommended starting dose of melatonin for this age group in a small amount (e.g., 4-6 drops), making it easy to administer alone or mixed with food or drink, and allowing for easy dose adjustments as the patient ages.

[0017] Thus, according to a first aspect, the present invention relates to a liquid formulation, preferably a suspension, comprising the following components: - Melatonin in particulate solid form, a vehicle, preferably an oil selected from medium chain triglycerides, vegetable oils and mixtures thereof, present in the liquid formulation in an amount of at least 80% w / v; and - viscosity increasing agents, preferably selected from silicon dioxide, such as colloidal silicon dioxide; compositions comprising at least 50% by weight of mono-, di- or triglycerides and mixtures thereof, for example compositions comprising glycerol monostearate or glyceryl dibehenate, gums such as xanthan gum, and mixtures thereof.

[0018] A second aspect of the present invention relates to a method for preparing a liquid formulation of the first aspect, the method comprising the steps of: a) mixing a liquid vehicle with a viscosity increasing agent in particulate solid form; b) Melatonin in particulate solid form is added to the mixture obtained in step a) and mixed.

[0019] A further aspect of the invention relates to a liquid formulation according to the invention for use as a pharmaceutical and / or food supplement.

[0020] A further aspect of the invention relates to a liquid formulation according to the invention for use in the prevention or treatment of a sleep disorder.

[0021] These aspects and preferred embodiments are described further below and defined in the claims. [Brief explanation of the drawings]

[0022] [Figure 1] 1 is a schematic diagram of a manufacturing process for a formulation according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention provides liquid melatonin formulations, methods for obtaining the formulations and uses thereof.

[0024] definition To facilitate the understanding of the invention, the meaning of some terms and expressions used in the context of the invention will be given below.

[0025] Melatonin (N-[2-(5-methoxy-1H-indol-3-yl)ethyl]acetamide (CAS 73-31-4), N-acetyl-5-methoxytryptamine, as used herein, is a compound of the formula: [ka]

[0026] Melatonin precipitates quickly when dispersed in water or oil. Minimizing settling of dispersed particles is a key requirement and a major technical challenge in the development of suspension formulations.

[0027] As used herein, the term "suspension" refers to a dispersed two-phase system in which one phase (the "internal phase") is dispersed as solid particles in another liquid phase (the "continuous phase" or "external phase"). By definition, these are thermodynamically unstable systems. Thus, when one phase is dispersed throughout the other, the system tends to return to a more energetically stable state, resulting in, for example, flocculation, sedimentation, coalescence, crystal growth, and caking.

[0028] When preparing stable pharmaceutical suspensions containing particulate active ingredients, the goal is to obtain a suspension that does not settle rapidly and / or can be easily reconstituted with gentle agitation to achieve a uniform dose of the active ingredient. However, maintaining a stable dispersion of particulate solids depends on a variety of factors, including Brownian motion of the particles, gravity, and steric and electrostatic forces between particles, making it impossible to know in advance which combination of active ingredient, excipients, and additives will provide the best stability.

[0029] As used herein, the term "excipient" or "additive" refers to an ingredient other than the active ingredient contained in a pharmaceutical or food supplement. Its intended function is to act as a carrier for the active ingredient and / or to contribute to improving product characteristics such as efficacy, bioavailability, stability, and patient acceptability, as well as to facilitate product manufacturing. The term "vehicle" refers to a carrier, consisting of one or more excipients, for an active ingredient in a liquid formulation.

[0030] The terms "% w / v" or "g / 100 mL" as applied to the formulations of the present invention refer to grams of a given substance in 100 mL of formulation, "% w / w" refers to grams of a given substance in 100 g of formulation, and "mg / mL" means milligrams of a given substance per mL of formulation.

[0031] The term " thickener " used herein refers to an agent that increases the viscosity of the vehicle, thereby minimizing the attraction and aggregation between particles, and allows dispersed particles to settle more slowly.Exemplary thickeners are natural gums such as xanthan gum, tragacanth gum, guar gum, etc.; polysaccharides such as alginate, pectin, agar, carrageenan, etc.; cellulose derivatives such as hydroxypropylmethylcellulose (HMPC), sodium carboxymethylcellulose (NaCMC), methylcellulose (MC), hydroxyethylcellulose (HEC), microcrystalline cellulose, colloidal silicon dioxide, monoglycerides, diglycerides and / or triglycerides, and their mixtures, and their mixtures.

[0032] As used herein, the term "preservative" refers to a compound that prevents or reduces physical and / or chemical deterioration of a composition, particularly a compound that protects the composition from microbial growth. Typically, preservatives according to the present invention are selected from the group consisting of methylparaben, ethylparaben, and propylparaben, benzoic acid, sodium benzoate, or mixtures thereof, or other pharmaceutically acceptable antimicrobial agents.

[0033] As used herein, the terms "flavoring agent" and / or "sweetener" refer to compounds that can be added to impart a desired taste or aroma, particularly sweetness. Exemplary flavoring agents and / or sweeteners include natural or artificial fruit flavors selected from mint, menthol, cinnamon, vanilla, chocolate, cherry, grape, orange, strawberry, or lemon.

[0034] Formulations according to the present invention In a first aspect, the present invention relates to a liquid formulation comprising: - Melatonin in particulate solid form, a vehicle, preferably an oil selected from medium chain triglycerides, vegetable oils, and mixtures thereof; and - viscosity increasing agents, preferably silicon dioxide, such as colloidal silicon dioxide; compositions comprising at least 50% by weight of mono-, di- or triglycerides or mixtures thereof, for example compositions comprising glycerol monostearate or glyceryl dibehenate; gums, such as xanthan gum; and mixtures thereof.

[0035] According to a preferred embodiment, the liquid formulation is in the form of a suspension, preferably a solid oil suspension.

[0036] The oil vehicle is present in the liquid formulations of the invention in an amount of at least 80% w / v, preferably at least 90% w / v, for example up to 99.9% w / v, preferably 97% w / v of the formulation, with the upper limit being 100% w / v multiplied by the density of the vehicle.

[0037] Alternatively, the oil vehicle is present in the liquid formulation of the invention in an amount of at least 80% w / w of the formulation, preferably at least 90% w / w, more preferably at least 95% w / w, even more preferably at least 96% w / w, for example up to 99.9% w / w, preferably up to 99.5% w / w, from these values. The upper limit for the amount of vehicle is 100% w / w minus the total weight percentage of all other ingredients in the formulation.

[0038] According to a preferred embodiment, the viscosity-increasing agent is contained in the liquid formulation of the present invention in an amount of 0.01 to 3% w / v, preferably 0.05 to 1% w / v, and more preferably 0.1 to 0.5% w / v. According to one embodiment, the liquid formulation further contains a vehicle in the above amount. Preferably, the liquid formulation is in the form of a suspension.

[0039] Alternatively, in the liquid formulation of the present invention, the viscosity-increasing agent is contained in an amount of 0.01 to 3% w / w, preferably 0.05 to 1% w / w, and more preferably 0.1 to 0.5% w / w. According to one embodiment, the liquid formulation further contains the above amount of a vehicle. Preferably, the liquid formulation is in the form of a suspension.

[0040] According to a preferred embodiment, the melatonin is in crystalline or amorphous form, preferably in crystalline form.

[0041] In certain embodiments, the melatonin in the formulations of the present invention has a relative particle size distribution D90 of less than 120 μm, preferably less than 60 μm. In certain embodiments, the melatonin has a relative particle size distribution D90 of greater than 1 μm, preferably greater than 5 μm. These maximum and minimum values ​​can also be combined to define a range.

[0042] In a particular embodiment, the relative particle size distribution D99 of the melatonin is less than 250 μm, preferably less than 220 μm.

[0043] In a particular embodiment, the melatonin has a relative particle size distribution D10 of less than 1 μm, preferably a relative particle size distribution D5 of less than 1 μm, otherwise less than 10% of the melatonin particles are less than 1 μm, in particular less than 5% are less than 1 μm.

[0044] In certain embodiments, the size of all melatonin particles in a formulation of the present invention is 420 μm or less, for example, between 0.5 and 400 μm.

[0045] The size and relative particle size distribution D90 can be measured, for example, by laser diffraction according to ISO 13320:2020 2nd Edition 2020-01.

[0046] The liquid formulations of the present invention can be used with a wide range of melatonin concentrations, for example, 0.1 to 40 mg / mL, although concentrations of about 0.5 to 35 mg / mL are preferred for ease of administration and greater suitability for pediatric patients.

[0047] In certain embodiments, the liquid formulations of the present invention comprise melatonin in an amount of about 1 to about 30 mg / mL, preferably about 2 to about 20 mg / mL, more preferably about 3 to about 15 mg / mL, and even more preferably about 5 to about 10 mg / mL.

[0048] Alternatively, melatonin is present in an amount of about 0.05 to about 3.5% w / v, preferably about 0.1 to about 3% w / v, more preferably about 0.2 to about 2% w / v, even more preferably about 0.3 to about 1.5% w / v, and even more preferably about 0.5 to about 1% w / v.

[0049] Melatonin is commercially available from a variety of chemical distributors, including Sigma-Aldrich (Ref. M5250), Tocris Bioscience (Ref. 3550), and Nutrifoods SLU (Ref. DIE-134).

[0050] According to a preferred embodiment, the oil vehicle in the above amount is preferably medium chain triglyceride (MCT), also known as medium chain triglyceride (MCT) oil. MCT has been found to be a beneficial vehicle because it is particularly effective in preventing the formulation from becoming rancid due to long-term storage. MCT is a C6-C 12 More specifically, MCTs are fatty acid esters of C6-C of glycerol. 12 Refers to one or more fatty acid di- or triesters. C6-C 12 Examples of fatty acids include caproic acid (C8), caprylic acid (C8), and capric acid (C 10 ), lauric acid (C 12 ) etc.

[0051] In a more preferred embodiment, MCTs are present in the liquid formulations of the invention in an amount of at least 80% w / v, preferably at least 90% w / v, for example from any of these values ​​up to 99.9% w / v, preferably up to 97% w / v of the formulation, for example 90-99% w / v, preferably 91-97% w / v, more preferably 93-96% w / v of the formulation.

[0052] Alternatively, the MCTs are present in an amount of at least 80% w / w of the formulation, more preferably at least 90% w / w, more preferably at least 95% w / w, even more preferably at least 96% w / w, for example from any of these values ​​up to 99.9% w / w, preferably up to 99.5% w / w, more preferably up to 99.0% w / w.

[0053] MCTs are typically obtained by processing coconut or palm oil. Processing typically involves three major steps: (1) extraction of fatty acids, usually after hydrolysis or saponification, (2) fractionation of fatty acids, and (3) re-esterification to triglycerides. Specific procedures are described, for example, in U.S. Patent 2015018295A.

[0054] Alternatively, MCTs are commercially available from various chemical distributors such as Croda (reference: GER2395), Gustav-Hees (reference: 4605), Gattefose (reference: 3139JV1).

[0055] According to another embodiment, the oil vehicle, preferably in the amounts mentioned above, is a vegetable oil.

[0056] In a preferred embodiment, the vegetable oil is corn oil, sunflower oil, safflower oil, sesame oil, soybean oil, flaxseed oil, olive oil, wheat oil, hemp oil, peanut oil, rapeseed oil, palm oil and their mixtures, particularly corn oil, sunflower oil, safflower oil, sesame oil, soybean oil and their mixtures.Preferably, soybean oil is useful vegetable oil because soybean oil is particularly effective in suppressing rancidity that occurs in formulations during long-term storage.

[0057] In a preferred embodiment, the vegetable oil has an initial peroxide value (at the time of preparing the liquid formulation of the present invention) of less than 10, preferably less than 8, more preferably less than 5. In a preferred embodiment, the peroxide value of the vegetable oil is 0.1 to 10, more preferably 0.5 to 8. The peroxide value can be measured according to European Pharmacopoeia 5.0, 2.5.5. Peroxide Value.

[0058] Vegetable oils are commercially available from a variety of chemical distributors, including Croda, Gustav-Hees, Gattefosse, Altaquimica, Quimidroga, and Infinity Choice.

[0059] According to one embodiment, the viscosity increasing agent is colloidal silicon dioxide; C of glycerol; 22 A composition comprising at least 70% by weight of a mixture of fatty acid mono- and diesters, C of glycerol 16 and C 18 a composition comprising at least 70% by weight of a mixture of fatty acid mono-, di-, and triesters; and xanthan gum.

[0060] In a preferred embodiment, the viscosity increasing agent is silicon dioxide, preferably colloidal silicon dioxide, preferably in the amounts described above.

[0061] Colloidal silicon dioxide refers to submicron (less than 1 micron in diameter) silicon dioxide, more specifically submicron (less than 1 micron in diameter) fumed silica, which is typically produced by the vapor-phase hydrolysis of silicon compounds such as silicon tetrachloride. The product itself is typically a light, loose, pale blue, odorless, tasteless amorphous powder, commercially available under the Aerosil or Cab-O-Sil trade names from a variety of manufacturers, including DeGussa and Evonik Industries.

[0062] Preferably, the colloidal silicon dioxide is 175 to 225 ml 2 / g, e.g., 200m 2 The colloidal silicon dioxide preferably has a specific surface area of ​​45 to 55 g / L, e.g., 50 g / L. The specific surface area can be measured according to the Brunauer, Emmett, and Teller (BET) method, more specifically according to ISO 9277:2010, 2nd Edition, 2010-09. More preferably, the colloidal silicon dioxide has a tamped density of 45 to 55 g / L, e.g., 50 g / L. The tamped density can be measured according to DIN EN ISO 787 / 11 (August 1983).

[0063] Such colloidal silicon dioxide products are known under the trade name Aerosil® 200 and include Aerosil® 200F (a food-grade version of Aerosil® 200) and Aerosil® 200 Pharma (a pharmaceutical-grade version of Aerosil® 200) and are commercially available from Evonik (reference number: 99033917).

[0064] According to one embodiment, the amount of silicon dioxide, preferably colloidal silicon dioxide, in the formulations of the invention is 0.01-3% w / v of the formulation, preferably 0.05-1% w / v, more preferably 0.1-0.5% w / v, even more preferably 0.1-0.3% w / v.

[0065] According to one embodiment, the thickening agent, preferably in the above-mentioned amount, is a thickening composition comprising a mono-, di-, or triglyceride, or a mixture thereof, preferably a mixture thereof, and preferably comprises at least 50% by weight, more preferably at least 70% by weight, and even more preferably at least 90% by weight of a mono-, di-, or triglyceride or a mixture thereof. Preferably, the mono-, di-, or triglyceride is a C16 to C22 fatty acid ester of glycerol. These glycerides may be saturated or unsaturated. Such a product can be obtained by transesterification of glycerol with a triglyceride.

[0066] The composition is preferably present in the formulation of the present invention in an amount of 0.05 to 3% w / v of the formulation, more preferably 0.1 to 1% w / v of the formulation.

[0067] According to a preferred embodiment, the viscosity increasing composition comprises a C 22The present invention relates to a mono-, di-, or triglyceride or mixture thereof, which is a fatty acid mono-, di-, or triester or a mixture thereof, and is preferably a C22 fatty acid mono-, di-, or triester of glycerol or a mixture thereof. More specifically, it is a behenic acid mono-, di-, or triester of glycerol or a mixture thereof, and is preferably a behenic acid mono-, di-, or triester of glycerol or a mixture thereof. Preferably, it is a mixture thereof, and more preferably, it is a C22 fatty acid mono-, di-, or triester of glycerol as the majority component by weight of the mixture. 22 It is a mixture containing a fatty acid diester. More specifically, it is a mixture containing glyceryl dibehenate as the majority component by weight of the mixture.

[0068] In any of these compositions, the combined weight of the monoesters and diesters of glycerol is at least 50%, preferably at least 70%, by weight of the viscosity increasing composition.

[0069] Most preferably, the viscosity increasing agent is a composition comprising a mixture of behenic acid mono- and diesters of glycerol in at least 70% by weight of the composition, wherein glyceryl dibehenate is the majority component by weight of the mixture.

[0070] These thickening agents, comprised of a mixture of glycerides, are commonly known as glyceryl dibehenate (or E471) and are available from DeGussa under the trademark Compritol and from Gattefose under the trademark (Ref. 7101PPD). Glyceryl dibehenate useful in the liquid formulations of the present invention is sold under the trademark Compritol E ATO.

[0071] According to another preferred embodiment, the viscosity increasing composition comprises a C 16 and / or C 18The present invention also includes mono-, di-, or triglycerides of fatty acid mono-, di-, or triesters, or mixtures thereof, preferably palmitic and / or stearic acid mono-, di-, or triesters of glycerol, or mixtures thereof. More preferably, the C 16 and / or C 18 The mono-, di-, and triglycerides are mixtures of fatty acid mono-, di-, and triesters, more specifically mixtures of palmitic and / or stearic acid mono-, di-, and triesters of glycerol. Preferably, the mono-, di-, or triglycerides or mixtures thereof are C glycerol mono-, di-, or triglycerides or mixtures thereof. 16 and / or C 18 It is a mixture of fatty acid mono-, di-, and triesters, more specifically a mixture of palmitic and stearic acid mono-, di-, and triesters of glycerol.

[0072] Preferably, in such compositions the fatty acid monoester of glycerol is present in an amount of at least 35% w / w of the composition, such as from 35 to 60% w / w, more preferably from 42 to 52% w / w.

[0073] Preferably, in such compositions the fatty acid diester of glycerol is present in an amount of at least 25% w / w of the composition, such as 25-50% w / w, more preferably 30-45% w / w.

[0074] Preferably, in such compositions the fatty acid triester of glycerol is present in an amount of at least 1% w / w of the composition, such as 1-20% w / w, more preferably 5-15% w / w.

[0075] In any of these compositions, the combined weight of the monoesters and diesters of glycerol is at least 50%, preferably at least 70%, by weight of the viscosity increasing composition.

[0076] C 16 and C 18The above-mentioned preferred conditions relating to compositions comprising mixtures of fatty acid mono-, di-, and triesters, more particularly mixtures of palmitic and stearic acid mono-, di-, and triesters of glycerol, can be used individually or in combination.

[0077] These compositions consist of a mixture of glycerides derived from palmitic and stearic acids, usually known as glycerol monostearate, and are sold, for example, by Gattefosse under the trademark Geleol (reference number 5749PPD).

[0078] According to a further embodiment, the viscosity increasing agent is a natural gum, more preferably xanthan gum, tragacanth gum or guar gum, even more preferably xanthan gum, preferably in the amounts described above.

[0079] Xanthan gum (also known as E415) is a polysaccharide produced from monosaccharides by fermentation using the bacterium Xanthomonas campestris. It is available commercially from various chemical distributors.

[0080] The preferred xanthan gum is fine particle size xanthan gum. "Fine particle size" herein means that at least 90%, preferably all, of the xanthan gum particles have a particle size of 180 μm or less. The particle size can be measured by passing 50 g of the product through an 80 mesh (180 μm) Tyler standard sieve using a Ro-Tap sieve shaker and shaking for 20 minutes. Such a product is commercially available from Azelis under the trade name Xantural 75 (trade name reference: BP106877) or from C.P. Kelkco under the same trade name (reference number 454-X).

[0081] According to one embodiment, the amount of xanthan gum in the formulation of the present invention is 0.01-1% w / v of the formulation, more preferably 0.05-0.2% w / v.

[0082] Importantly, the inventors have found that combining an oil vehicle with a suspending agent improves the physical stability of melatonin suspensions without compromising other characteristics such as chemical stability, organoleptic properties, and / or microbial activity.

[0083] According to certain embodiments, the liquid formulations, preferably suspensions, of the present invention may further comprise a preservative selected from the group of methylparaben, ethylparaben and propylparaben, benzoic acid, sodium benzoate, or mixtures thereof, or other pharmaceutically acceptable antimicrobial agents.

[0084] However, surprisingly, it is not necessary to add a preservative to avoid microbial contamination of the liquid formulation of the present invention. Thus, in a particularly preferred embodiment, the liquid formulation of the present invention does not contain any one or more, for example, all, of the preservatives listed above. More preferably, the liquid formulation of the present invention does not contain a preservative.

[0085] According to a particular embodiment, the liquid formulations, preferably suspensions, of the present invention may further comprise sweeteners and / or flavoring agents.

[0086] Surprisingly, however, the addition of neither sweeteners nor flavorings is necessary to obtain an organoleptically pleasing liquid formulation. Thus, in a particularly preferred embodiment, the liquid formulation of the present invention does not contain any sweeteners or flavorings.

[0087] The liquid formulation of the present invention may contain other excipients. However, the inventors have found that the formulation of the present invention has excellent properties even without additional excipients. Therefore, according to one embodiment, the liquid formulation does not contain any other excipients other than the vehicle and the viscosity-increasing agent.

[0088] In certain embodiments, the formulations of the present invention do not contain a surfactant selected from polyoxyethanyl tocopheryl sebacate (PTS), polyoxyethanyl sitosterol sebacate (PSS), polyoxyethanyl cholesterol sebacate (PCS), polyoxyethanyl ubiquinol sebacate (PQS), and combinations thereof. In one embodiment, the formulations of the present invention do not contain a surfactant in addition to the vehicle and / or viscosity-increasing agent.

[0089] According to a particular embodiment, the formulation of the present invention does not comprise a gelling agent in addition to the vehicle and / or viscosity increasing agent and is not in the form of a gel.

[0090] According to a particular embodiment, the formulation of the present invention is free of acrylic polymers, more particularly free of polymers.

[0091] According to one embodiment, the formulation of the invention comprises only melatonin and, optionally, one further active ingredient. Preferably, the formulation of the invention comprises melatonin as the only active ingredient.

[0092] According to one embodiment, the formulations of the invention are tetrahydrocannabinol-free, preferably cannabinoid-free, more preferably cannabinoid-free, cannabinoid extract (i.e. an extract from the cannabis plant which comprises cannabinoids), terpenes and / or terpene extract (i.e. an extract from the plant which comprises terpenes), even more preferably cannabinoid-free, cannabinoid extract, terpene, terpene extract, ethyl pyruvate, caffeine and / or resveratrol-free.

[0093] According to one embodiment, the formulation of the present invention is insulin-free.

[0094] According to one embodiment, the formulations of the present invention do not contain unsubstituted or substituted diindolylmethanes, and preferably do not contain compounds containing two or more unsubstituted or substituted indole groups.

[0095] According to one embodiment, the formulation of the present invention does not contain pyrroloquinoline quinone, preferably does not contain pyrroloquinoline quinone or its derivatives, more preferably does not contain pyrroloquinoline quinone of the following formula or its derivatives: [ka] (In the formula, R1, R2, and R3 are independently a hydrogen atom, an alkyl group, an alkenyl group, a haloalkyl group, a benzyl group, or an alkoxycarbonylalkyl group.)

[0096] According to one embodiment, the formulation of the invention does not contain cyclosporin A, and preferably does not contain any peptides.

[0097] According to one embodiment, the formulation of the present invention does not contain chitosan salts salified with N-acetylcysteine ​​(NAC), and preferably does not contain chitosan or its salts.

[0098] In a more specific embodiment, the liquid formulation consists of: - Melatonin in particulate solid form; - a vehicle according to any of the above embodiments; and - a viscosity increasing agent according to any of the above embodiments.

[0099] According to one embodiment, the formulation of the invention comprises, and in particular consists of: - melatonin in particulate solid form, preferably in an amount of 1 to 30 mg / mL, preferably 2 to 20 mg / mL, more preferably 3 to 15 mg / mL, even more preferably 5 to 10 mg / mL in the formulation, a vehicle which is an oil, preferably wherein the oil is selected from medium chain triglycerides, vegetable oils and mixtures thereof, preferably in an amount of at least 80% w / v, preferably at least 90% w / v, for example from any of these values ​​up to 99.9% w / v, preferably up to 97% w / v, a viscosity increasing agent (preferably silicon dioxide (preferably colloidal silicon dioxide); a composition comprising at least 70% by weight of a mixture of mono-, di-, or triglycerides (said mono-, di-, or triglycerides being C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 18 -C 19 -C 20 -C 21 -C 22 -C 23 -C 24 -C 25 -C 26 -C 27 -C 28 -C 29 -C 30 -C 31 -C 32 -C 33 -C 34 -C 35 -C 36 -C 37 -C 38 -C 39 -C 40 -C 4 16 ~C 22 fatty acid esters; gums such as xanthan gum; and mixtures thereof), preferably in an amount of 0.01 to 3% w / v, more preferably 0.05 to 1% w / v, and even more preferably 0.1 to 0.5% w / v of the formulation.

[0100] According to one embodiment, the formulation of the invention comprises, and in particular consists of: - melatonin in particulate solid form in the formulation in an amount of 1 to 30 mg / mL, preferably 2 to 20 mg / mL, more preferably 3 to 15 mg / mL, even more preferably 5 to 10 mg / mL, - a medium chain triglyceride vehicle in an amount of at least 80% w / v, preferably at least 90% w / v, more preferably 90-99% w / v, even more preferably 91-97% w / v, even more preferably 93-96% w / v of the formulation, a composition comprising a viscosity increasing agent, preferably silicon dioxide, preferably colloidal silicon dioxide, at least 70% by weight of a mixture of mono-, di-, or triglycerides, said mono-, di-, or triglycerides being C of glycerol; 16 ~C 22 fatty acid esters, gums such as xanthan gum, and mixtures thereof), preferably in an amount of 0.01-3% w / v of the formulation, more preferably 0.05-1% w / v, and even more preferably

[0101] In another embodiment, the formulation of the invention comprises, and in particular consists of: - melatonin in particulate solid form, preferably in an amount of 1 to 30 mg / mL, preferably 2 to 20 mg / mL, more preferably 3 to 15 mg / mL, even more preferably 5 to 10 mg / mL in the formulation, a vehicle which is an oil, preferably the oil is selected from the following: medium chain triglycerides, vegetable oils and mixtures thereof, preferably in an amount of at least 80% w / v, preferably at least 90% w / v, for example from any of these values ​​up to 99.9% w / v, preferably up to 97% w / v, - A viscosity increasing agent, i.e., colloidal silicon dioxide, is present in the formulation in an amount of preferably 0.01 to 3% w / v, more preferably 0.05 to 1% w / v, even more preferably 0.1 to 0.5% w / v, and even more preferably 0.1 to 0.3% w / v.

[0102] According to one embodiment, the formulation of the invention comprises, and in particular consists of: - melatonin in particulate solid form, in an amount of 1 to 30 mg / mL, preferably 2 to 20 mg / mL, more preferably 3 to 15 mg / mL, even more preferably 5 to 10 mg / mL in the formulation; - a medium chain triglyceride vehicle in an amount of at least 80% w / v, preferably at least 90% w / v, more preferably 90-99% w / v, even more preferably 91-97% w / v, even more preferably 93-96% w / v of the formulation, - A viscosity increasing agent, i.e. colloidal silicon dioxide, is present in the formulation in an amount of preferably 0.01 to 3% w / v, preferably 0.05 to 1% w / v, more preferably 0.1 to 0.5% w / v, even more preferably 0.1 to 0.3% w / v.

[0103] According to a preferred embodiment, the formulation of the invention comprises, and in particular consists of: - melatonin in particulate solid form in an amount of 2 to 20 mg / mL, preferably 3 to 15 mg / mL, more preferably 5 to 10 mg / mL in the formulation, - a vehicle, which is a medium chain triglyceride in an amount of 90-99% w / v, preferably 91-97% w / v, more preferably 93-96% w / v of the formulation; and - A viscosity increasing agent, which is colloidal silicon dioxide in an amount of 0.1-0.5% w / v, preferably 0.1-0.3% w / v of the formulation.

[0104] In a preferred embodiment, the formulation of the invention comprises, and in particular consists of: melatonin in particulate solid form in the formulation at 3 to 15 mg / mL, preferably 5 to 10 mg / mL; - Medium chain triglycerides at 91-97% w / v of the formulation, - Colloidal silicon dioxide at 0.1-0.3% w / v of the formulation.

[0105] The relative density of the formulation of the present invention is 0.9 to 1 g / mL, preferably 0.93 to 0.96 mg / mL. The relative density can be measured using a pycnometer or hydrometer (20°C). More specifically, the relative density can be measured according to European Pharmacopoeia 5.0, 2.2.5 "Relative Density."

[0106] method The formulations of the present invention can be prepared according to any known method in the prior art.

[0107] In a second aspect, the present invention relates to a method for preparing a formulation, the method comprising the steps of: a) Mixing a liquid vehicle and a solid viscosity increasing agent. b) Melatonin in particulate solid form is added to the mixture obtained in step a) and mixed.

[0108] The present invention therefore relates to a method for preparing a formulation, said method not comprising, prior to step a) or b), a step of preparing a melatonin composition comprising melatonin and an excipient, said melatonin composition being solid, in particular said melatonin composition being a powder obtained by a freeze-drying process.

[0109] In particular, the method does not include a step of preparing a melatonin composition comprising melatonin and a suspending agent prior to step a) or b). In particular, the melatonin composition is a powder obtained by freeze-drying. More particularly, the suspending agent is hydrolyzed beeswax, and even more particularly, the hydrolyzed beeswax is obtained from natural beeswax by sequentially subjecting it to saponification and acidification with at least one food-grade organic acid.

[0110] According to a preferred embodiment, the mixing in step a) is carried out in a suitable tank equipped with a stirrer until a homogeneous mixture is obtained.

[0111] Optionally, the method includes adding a sweetener and / or a flavoring and / or a preservative in any of the above steps. Preferably, the method includes adding no sweetener and no flavoring, and more preferably, the method includes adding no sweetener, no flavoring, and no preservative.

[0112] According to a preferred embodiment, the method further comprises step c) of adding a liquid vehicle (preferably in an amount appropriate for the final volume) and mixing. Preferably, the liquid vehicle is the same as the liquid vehicle used in step a).

[0113] In particular, the present invention relates to a method for preparing the formulation of the present invention, said method comprising the steps of: a) Mixing a liquid vehicle and a solid viscosity increasing agent. b) Melatonin in particulate solid form is added to the mixture obtained in step a) and mixed. c) Add liquid vehicle to final volume and mix.

[0114] According to a preferred embodiment, the method includes a final step of homogenizing the resulting mixture.

[0115] In particular, the present invention relates to a method for preparing the formulation of the present invention, said method comprising the steps of: a) Mixing a liquid vehicle and a solid viscosity increasing agent. b) Melatonin in particulate solid form is added to the mixture obtained in step a) and mixed. c) Add liquid vehicle to final volume and mix. d) homogenizing the mixture obtained in step c).

[0116] As used herein, the term "homogenized" means that the final mixture has substantially the same composition throughout. In particular, a mixture is considered homogenous if samples of the formulation prepared from different parts of the container, e.g., the top, middle, and bottom, differ in melatonin concentration by no more than 10%.

[0117] The meaning and preferred embodiments of each component of the formulation are the same as those described for the formulation in the first aspect of the present invention. In a preferred embodiment, the viscosity-increasing agent is colloidal silicon dioxide, and the vehicle is a medium-chain triglyceride or a mixture of medium-chain triglycerides.

[0118] In another aspect, the invention relates to a formulation obtainable by any of the methods described herein.

[0119] Purpose In a further aspect, the present invention relates to a formulation of the invention as defined in any of the above embodiments for use as a pharmaceutical and / or food supplement.

[0120] Another aspect of the invention relates to a liquid formulation of the invention as defined in any of the above embodiments for use in the prevention or treatment of sleep disorders, such as insomnia and circadian rhythm sleep-wake disorders.

[0121] As used herein, the terms "treatment" or "treating" refer to the administration of a formulation of the present invention to ameliorate or eliminate a condition or disorder, or one or more symptoms associated with that condition or disorder. "Treatment" also includes ameliorating or eliminating the physiological sequelae of the condition.

[0122] The term "prevention" or "preventing" in the context of this specification means reducing the risk of acquiring or developing a condition or disorder, or one or more symptoms associated with that condition or disorder.

[0123] Circadian rhythm sleep disorders (formally circadian rhythm sleep-wake disorders) are a group of conditions related to malfunction or irregularities in the body's internal clock. Examples of these disorders range from mild conditions such as jet lag to severe conditions such as delayed sleep-wake disorder, early sleep-wake disorder, irregular sleep-wake rhythm disorder, and shift work disorder.

[0124] The above aspect may be formulated as the use of a formulation of the invention as defined in any of the above embodiments in the manufacture of a medicament and / or dietary supplement for the prevention or treatment of sleep disorders, such as insomnia and circadian rhythm sleep-wake disorders.

[0125] The above aspects can be formulated such that the formulation of the invention as defined in any of the above embodiments is used as a pharmaceutical and / or dietary supplement for the prevention or treatment of sleep disorders, such as insomnia and circadian rhythm sleep-wake disorders.

[0126] The above aspects can be formulated as a method for treating or preventing sleep disorders, such as insomnia and circadian rhythm sleep-wake disorders, which method comprises administering a formulation of the invention as defined in any of the above embodiments to a patient in need of such prevention or treatment.

[0127] Preferably, in any of the above embodiments, the formulations of the present invention are suitable for oral administration, more particularly oral administration by ingestion. More particularly, in any of the above medical use embodiments, the formulations of the present invention are administered by the oral route, more particularly by ingestion.

[0128] According to one embodiment, in any of the above medical use embodiments, the formulations of the present invention are administered to subjects other than adults, more particularly to subjects under the age of 3. [Example]

[0129] The following examples are merely illustrative of certain embodiments of the present invention and are not intended to limit the invention in any way.

[0130] Example 1. The formulation of the present invention was prepared by first transferring 304.5 kg of liquid medium-chain triglycerides to a suitable tank, then adding 0.6 kg of solid silicon dioxide to the tank and stirring at 2900 rpm for 15 minutes, followed by adding 4.0 kg of granular solid melatonin to the tank and stirring at 2900 rpm. Finally, 76.1 kg of liquid medium-chain triglycerides was added to the tank and stirring at 2900 rpm for 45 minutes.

[0131] Example 2. Melatonin Oral Suspension Component Amount (g / 100 mL-% w / v) Melatonin 0.90 Colloidal silicon dioxide 0.15 Medium Chain Triglycerides 100ml

[0132] Example 3. Melatonin Oral Suspension Component Amount (g / 100 mL-% w / v) Melatonin 0.60 Colloidal silicon dioxide 0.15 Medium Chain Triglycerides 100ml

[0133] Example 4. Melatonin Oral Suspension Component Amount (g / 100 mL-% w / v) Melatonin 0.90 Glycerol Monostearate (Geleol) 0.50 Medium Chain Triglycerides 100ml

[0134] Example 5. Melatonin Oral Suspension Component Amount (g / 100 mL-% w / v) Melatonin 0.90 Xanthan gum (Xantural 75) 0.12 Medium Chain Triglycerides 100ml

[0135] Example 6. Melatonin oral suspension Component Amount (g / 100 mL-% w / v) Melatonin 0.90 Glyceryl Dibehenate (Compritol E ATO) 0.50 Soybean oil (up to 100ml)

[0136] Example 7. Stability test For purposes of the present invention, the stability of two melatonin oil suspensions in different containers was tested.

[0137] The suspensions will be prepared as described above, filled into the packaging materials described below, and stored under the conditions described below to determine whether the tested multi-dose suspensions remain stable for 6 months.

[0138] [Table 1]

[0139] L21 / 05 is the formulation of Example 3 and L21 / 06 is the formulation of Example 2.

[0140] After 6 months of storage, the physicochemical stability of the suspensions was verified by checking their appearance, sensory properties, redispersibility, and by measuring their density (Ph Eur. 2.2.5.) and melatonin concentration (HPLC / UV spectroscopy).

[0141] [Table 2]

[0142] [Table 3]

[0143] [Table 4]

[0144] Results show that the liquid formulation of the present invention remains stable for at least six months under all conditions tested.

[0145] Example 8. Additional Compositions Further melatonin oral suspensions according to the present invention were prepared. In these suspensions, melatonin was present at a concentration of 9 mg / mL. Each suspension represented the following combination of a specific oil vehicle and a specific viscosity-increasing agent (% w / v, i.e., g / 100 mL):

[0146] [Table 5]

[0147] Example 9. Stability testing of additional compositions The composition of Example 8 was subjected to stability testing similar to that of Example 7. Tested after 3, 6 and 12 months storage at 40°C / 75%RH. Each composition was in the form of a clear oily suspension with visible solid particles in suspension and / or precipitate at all time points and conditions tested. Each composition exhibited uniformly suspended visible solid particles without sediment after redispersion at all time points and conditions tested. Each composition exhibited suitable density values ​​within the range of 0.93–0.96 g / mL at all time points and conditions tested. Each composition exhibited melatonin concentrations ranging from 7.2 to 10.8 mg / ml at all time points and conditions tested.

[0148] Based on these results, it can be concluded that the liquid formulation of the present invention remains stable for at least six months under all conditions studied.

Claims

1. A liquid formulation containing: - Melatonin in particulate solid form, a vehicle which is an oil, present in the liquid formulation in an amount of at least 80% w / v, and - Viscosity increasing agents.

2. 10. The formulation of claim 1, wherein the formulation is in the form of a suspension.

3. 4. The formulation according to any one of claims 1 to 3, wherein the amount of melatonin is 1 to 30 mg / mL, preferably 2 to 20 mg / mL, more preferably 3 to 15 mg / mL, even more preferably 5 to 10 mg / mL.

4. The formulation of any one of claims 1 to 3, wherein the oil vehicle is selected from medium chain triglycerides and vegetable oils.

5. 5. The formulation of claim 4, wherein the oil vehicle is a medium chain triglyceride.

6. A formulation according to any one of claims 1 to 5, wherein the amount of oil contained in the liquid formulation is at least 90% w / w.

7. The viscosity increasing agent comprises colloidal silicon dioxide; a mixture of at least 70% by weight of monoglycerides, diglycerides and / or triglycerides, wherein the monoglycerides, diglycerides or triglycerides are at least 70% by weight of glycerol C １６ ~C ２２ The formulation of any one of claims 1 to 6, wherein the composition is selected from fatty acid esters; and xanthan gum.

8. 8. A formulation according to any one of claims 1 to 7, wherein the viscosity increasing agent is colloidal silicon dioxide and is present in the formulation in an amount of 0.01 to 3% w / v, preferably 0.05 to 1% w / v, more preferably 0.1 to 0.5% w / v, even more preferably 0.1 to 0.3% w / v.

9. The viscosity increasing agent is a composition comprising a mixture of at least 70% by weight of monoglycerides, diglycerides and / or triglycerides, wherein the monoglycerides, diglycerides or triglycerides are at least 70% by weight of glycerol C １６ ~C ２２ 9. A formulation according to any one of claims 1 to 8, wherein the composition is selected from fatty acid esters, said composition being present in the formulation in an amount of 0.05 to 3% w / v of the formulation, more preferably 0.1 to 1% w / v.

10. The viscosity increasing agent is a composition comprising a mixture of at least 70% by weight of monoglycerides and diglycerides, wherein the monoglycerides and diglycerides are at least 70% by weight of glycerol. ２２ The formulation according to any one of claims 1 to 9, which is a fatty acid ester.

11. The viscosity increasing agent is a composition comprising a mixture of at least 70% by weight of mono-, di-, and triglycerides, wherein the mono-, di-, and triglycerides are C16 and / or C2 of glycerol. １８ The formulation according to any one of claims 1 to 10, which is a fatty acid ester.

12. - melatonin in particulate solid form in an amount of 2 to 20 mg / mL, preferably 3 to 15 mg / mL; medium chain triglycerides in an amount of 90 to 99% w / v, preferably 91 to 97% w / v, colloidal silicon dioxide in an amount of 0.1 to 0.5% w / v, preferably 0.1 to 0.3% w / v 2. The formulation of claim 1, comprising:

13. The formulation according to any one of claims 1 to 12, which is in a form suitable for oral administration.

14. A method for preparing a formulation according to any one of claims 1 to 13, comprising the steps of: - Mixing a liquid oil vehicle with a solid viscosity increasing agent, - adding particulate melatonin to the mixture obtained in step a) and mixing. The method comprising:

15. The formulation according to any one of claims 1 to 13 for use in the prevention and / or treatment of insomnia and circadian rhythm sleep-wake disorders.

16. 16. The formulation for use according to claim 15, wherein the formulation is administered orally.

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