Sustained-release melatonin granules, combinations comprising melatonin, pharmaceutical compositions and dietary supplements containing same, and their use in treating insomnia and reducing time required to fall asleep

Abstract

The invention aims to provide sustained-release melatonin granules, a pharmaceutical composition and a dietary supplement containing the granules, and application of the sustained-release melatonin granules in treatment of sleep disorders and reduction of time required for falling asleep, especially application of the sustained-release melatonin granules in treatment of primary insomnia. Another purpose of the invention is to provide a composition consisting of melatonin, sodium alginate and calcium lactate and application of the composition in treatment of sleep disorders, especially primary insomnia.

Description

[0001] The object of this invention is to provide sustained-release melatonin granules, pharmaceutical compositions comprising said granules, and dietary supplements, as well as their use in treating sleep disorders and for reducing the time required to fall asleep, particularly in treating primary insomnia. Another object of this invention is to provide a combination of melatonin, sodium alginate, and calcium lactate, and its use in treating sleep disorders, particularly primary insomnia. Background Technology

[0002] The International Classification of Sleep Disorders defines insomnia as: difficulty falling asleep, duration of sleep, consolidation of sleep, or quality of sleep, despite having sufficient opportunities for sleep, resulting in some form of daytime disturbance (e.g., fatigue, decreased energy, daytime sleepiness, and mood disorder).

[0003] Insomnia can be primary or secondary. Primary insomnia can involve both intrinsic and extrinsic factors but is not considered a secondary symptom of other diseases. Secondary insomnia occurs when insomnia is a result of medical or mental illness, other sleep disorders, or substance abuse.

[0004] The term "primary insomnia" (used in the International Classification of Diseases (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV)) refers to a chronic disorder that lasts for at least three months and occurs at least three times a week. When the disorder meets the symptom criteria but lasts for less than three months, it is called acute short-term insomnia.

[0005] Different symptoms of insomnia can appear at different times during sleep.

[0006] For example:

[0007] • Sleep onset insomnia (or initial insomnia) involves difficulty falling asleep before bedtime;

[0008] • Sleep maintenance insomnia (or mid-term insomnia) involves frequent or persistent awakenings during the night;

[0009] • Later-stage insomnia involves the inability to fall back asleep after waking up in the morning;

[0010] Non-restorative sleep, a disorder of poor sleep quality, is a common sleep disorder in which an individual is unable to feel refreshed upon waking despite sufficient sleep duration. It is usually associated with difficulty initiating or maintaining sleep and can also occur concurrently with other sleep disorders, such as breathing-related sleep disorders.

[0011] Cognitive impairment can include difficulty with attention, concentration, and memory, and can even affect performance on simple manual skills. Related mood disorders are often described as irritability or mood instability, with depression or anxiety being less common. Not everyone with nighttime sleep disorders experiences anxiety or functional impairment. For example, healthy older adults often experience interrupted sleep continuity but still consider themselves good sleepers. A diagnosis of insomnia disorder should only be made for those who experience severe daytime discomfort or functional impairment due to difficulty sleeping at night.

[0012] Insomnia disorder can be diagnosed if it presents as an independent condition or occurs concurrently with other mental disorders (such as major depressive disorder), conditions (such as pain), or other sleep disorders (such as breathing-related sleep disorders).

[0013] Insomnia symptoms can occur at any stage of life, but the first onset is most common in adolescence. Less frequently, insomnia begins in childhood or adolescence. Insomnia is a condition more common in women than in men, with the first onset often associated with newborn birth or menopause. Although the prevalence is higher in older women, polysomnography studies have shown that older women maintain better sleep continuity and slow-wave sleep compared to older men.

[0014] Short-term insomnia affects 30% to 50% of the population.

[0015] It is estimated that the prevalence of chronic insomnia in industrialized countries is at least 5% to 10% by weight. Chronic insomnia is associated with numerous adverse effects on function, health, and quality of life. Increased rates of absenteeism, workplace accidents, and motor vehicle accidents have been widely reported. Numerous studies have identified persistent insomnia as a significant risk factor for the development of mental disorders, particularly mood disorders. This condition is also associated with an increased risk of relapse into depression and alcoholism, as well as adverse effects on people with chronic pain. Recent studies have shown that chronic insomnia is associated with an increased risk of cardiovascular disease. In particular, objectively short sleep duration is a significant risk factor for the development of hypertension. Regulation (EU) 432 / 2012 establishes a list of health claims for vitamins, minerals, and other substances authorized under Article 13.1 of Regulation (EC) 1924 / 2006. Substances authorized to make such claims include melatonin.

[0016] The list above includes “conditions of use” for each substance, indicating the required quantitative intake as stated, as well as any “use restrictions” and / or additional warnings.

[0017] In other words, the quantitative intake of substances authorized by health claims should be considered to have "physiological" value because they are intended to promote normal bodily functions. Regarding melatonin, Regulation (EU) 432 / 2012 allows two types of claims:

[0018] - By indicating on the label that consumers can achieve beneficial effects by taking at least 0.5mg of the substance before bedtime on the first day of the trip and in the days following arrival at the destination, it can help alleviate the effects of "jet lag";

[0019] - By indicating to consumers on the label that taking 1mg of the substance before bedtime will have beneficial effects, it can help reduce the time needed to fall asleep.

[0020] Therefore, based on the scientific assessment of EFSA, the level of melatonin that is useful for physiological effects has now been determined, and products based on the same substance are authorized in the EU market as medicines with a daily dose of 2 mg.

[0021] Melatonin is a hormone involved in the regulation of circadian rhythms. In mammals, melatonin levels are higher at night and lower during the day. For this reason, melatonin is commonly used to treat sleep disorders, particularly insomnia, and its administration is especially suitable for inducing sleep in individuals experiencing severe difficulty falling asleep. However, due to the short half-life of the melatonin molecule, most conventional melatonin formulations are characterized by rapid release, and therefore, the active ingredient is rapidly metabolized. Consequently, these formulations provide a peak melatonin release above physiological levels within 1 to 2 hours after administration, subsequently gradually returning to normal levels. This rapid-release formulation cannot reproduce the time course of endogenous melatonin production.

[0022] Documents WO2018 / 106280A1 and WO2012 / 103411A2 describe particles containing melatonin and excipients, but do not describe particles containing sodium alginate and calcium lactate in addition to melatonin.

[0023] Document CN 114259490 A describes a melatonin formulation comprising an immediate-release portion and an enteric-coated sustained-release portion. The immediate-release portion comprises, by weight, 0.04 to 0.12 parts melatonin and 20 to 140 parts diluent. The enteric-coated sustained-release portion comprises 0.001 to 0.01 parts melatonin, 0.4 to 20 parts sustained-release material, 12 to 90 parts diluent, and 0.6 to 24 parts coating agent. The diluent is composed of at least one of the following: microcrystalline cellulose, lactose, mannitol, white sugar, dextrin, sugar alcohol, oligosaccharides, starch, and pregelatinized starch. The extended-release material is at least one of the following: hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, sodium carboxymethyl cellulose, sodium alginate, and acrylic resin. The coating agent is an enteric film coating agent. The outer layer of the sustained-release enteric-coated portion is coated with an enteric coating agent. Particles containing sodium alginate and calcium lactate in addition to melatonin have not yet been described.

[0024] Therefore, it should be understood that there is still a need to provide new and original melatonin compositions that can provide an appropriate duration of action, thus producing a more lasting effect during sleep and thus better treating sleep disorders.

[0025] Purpose of the invention

[0026] The first object of the present invention is to provide a particle that provides a useful, acceptable and effective amount of melatonin with a controlled, prolonged release time to a treated subject.

[0027] Another object of the present invention is to provide a method for preparing the particles of the present invention.

[0028] Another object of the present invention is to provide a pharmaceutical composition and / or dietary supplement comprising the particles of the present invention, and its use in treating sleep disorders and for reducing the time required to fall asleep.

[0029] This invention also refers to Figure 1 -2 (A and B) are reported and described, and the results of the tests are shown in the figure:

[0030] Figure 1 The results show the behavior of the two types of particles immediately after being poured into 0.1N HCl.

[0031] Figure 2A and 2B The diagram shows the behavior of the two types of particles immediately after being poured into 0.1N HCl (top view). Summary of the Invention

[0032] Through long-term and in-depth research and development activities, the applicant has developed a melatonin-based granule that is easy to administer and has no side effects. It continuously releases melatonin over time after administration, which is optimal for treating sleep disorders and maintaining a state of sleep.

[0033] Therefore, according to one aspect of the invention, an object of the invention is to provide a slow-release, gradually releasing particle comprising or composed of melatonin, sodium alginate and calcium lactate.

[0034] Alginate in algae is insoluble. It needs to be converted into, for example, sodium alginate or other soluble alginate.

[0035] The applicant selected sodium alginate from all soluble alginates and, after several attempts, found that combining sodium alginate with soluble divalent cation salts was useful.

[0036] The applicant selected Ca from all possible divalent cations. 2+Both affinity and safety were considered. Calcium lactate was selected from all soluble divalent cation salts after careful screening, taking into account its physicochemical properties and the other components (sodium alginate and melatonin) commonly present in the granule composition for the purposes of this invention. Calcium lactate was chosen from all possible calcium salts because it possesses numerous properties that make it the preferred salt for preparing the melatonin granules for the purposes of this invention, namely: i) good water solubility; ii) a pH range of 6 to 8 for a 5% calcium lactate aqueous solution; iii) Ca 2+ The titer is 12% to 18%, with a preferred range of 13.4% to 14.5%.

[0037] All components of the particles of this invention are technically known and commercially available.

[0038] Preferably, the melatonin titer is 95% or higher, more preferably 98% or higher, and even more preferably 99% or higher, for example 99.5%.

[0039] According to a preferred embodiment, the melatonin content in the particles of the present invention is 1% to 20% by weight relative to the total weight of the particles, preferably 1.5% to 15% by weight, more preferably 2% to 10% by weight, for example 2.5% by weight; 3% by weight; 3.5% by weight; 4% by weight; 4.5% by weight or 5% by weight.

[0040] According to a preferred embodiment, the sodium alginate content in the particles of the present invention is 20% to 60% by weight, preferably 40% to 55% by weight, more preferably 45% to 50% by weight, for example about 46% by weight; 47% by weight; 48% by weight; or 49% by weight, relative to the total weight of the particles.

[0041] According to a preferred embodiment, the calcium lactate content in the particles of the present invention is 30% to 60% by weight, preferably 40% to 55% by weight, more preferably 45% to 50% by weight, for example about 46% by weight; 47% by weight; 48% by weight; 49% by weight, relative to the total weight of the particles.

[0042] Preferably, the particles of the present invention comprise:

[0043] -1% to 20% by weight, preferably 1.5% to 15% by weight, more preferably 2% to 10% by weight, relative to the total weight of the particles;

[0044] - 20% to 60% by weight, preferably 40% to 55% by weight, more preferably 45% to 50% by weight, relative to the total weight of the particles, for example, about 49% by weight of sodium alginate;

[0045] - 30% to 60% by weight, preferably 40% to 55% by weight, more preferably 45% to 55% by weight, for example about 49% to 50% by weight of calcium lactate relative to the total weight of the particles.

[0046] According to another aspect of the present invention, an object of the present invention is to provide a method for preparing the particles of the present invention, which includes or consists of the following steps:

[0047] a. The mixture is wet-granulated to form particles of: (i) melatonin, in an amount of 1% to 20% by weight, for example about 2% or 10% by weight, relative to the total weight of the particles; (ii) sodium alginate, in an amount of 20% to 60% by weight, for example about 45% or 49% by weight, relative to the total weight of the particles; and (iii) calcium lactate, in an amount of 30% to 60% by weight, for example 45% or 49% by weight, relative to the total weight of the particles, to form particles to be coated particles.

[0048] b. Coating the particles obtained in step (a) through two consecutive steps to obtain coated particles:

[0049] b' Granulation of the particles in step (a) using calcium lactate; and

[0050] b" Granulate the particles in step (b') using sodium alginate.

[0051] In step (a), according to known techniques, 1% to 20% by weight of melatonin is mixed with 20% to 60% by weight of sodium alginate and 30% to 60% by weight of calcium lactate and water, and wet granulation is performed.

[0052] The particles obtained in step (a) are dried, for example in an oven, preferably at a temperature of 40°C to 80°C, more preferably at 50°C to 70°C, such as at 60°C, for a duration preferably of 2 to 12 hours, more preferably of 4 to 10 hours, such as 8 hours. Preferably, the dried particles are subjected to a calibration step, for example using a sieve or screen with a mesh size of 0.5 mm to 2.5 mm, preferably 1 mm to 2 mm, such as 1.2 mm, 1.4 mm or 1.6 mm.

[0053] Then, the dried granules from step (a) are coated via two consecutive granulation steps (b') and (b') in step (b); first, the granules are treated with calcium lactate in step (b') to obtain calcium lactate-coated granules, and then further coated with sodium alginate in step (b'). The granules obtained after each step (a), (b'), and (b') are dried according to known techniques.

[0054] According to a preferred embodiment, the granulation in step (b) can be fluidized bed granulation or slurry granulation.

[0055] Alternatively, the preparation method of the particles of the present invention can be completed by single-step granulation of a mixture of melatonin, sodium alginate and calcium lactate, followed by a single coating step.

[0056] According to another aspect of the present invention, an object of the present invention is to provide a method for preparing the particles of the present invention, which includes or consists of the following steps:

[0057] a. The mixture is wet-granulated to form particles containing (i) melatonin in an amount of 1% to 20% by weight, for example about 2% or 10% by weight, relative to the total weight of the particles; (ii) sodium alginate in an amount of 20% to 60% by weight, for example about 45% or 49% by weight, relative to the total weight of the particles; and (iii) calcium lactate in an amount of 30% to 60% by weight, for example 45% or 49% by weight, relative to the total weight of the particles, to form particles to be coated particles.

[0058] b. The particles obtained from step (a) are coated using a mixture of sodium alginate and calcium lactate in a one-step coating step to obtain coated particles.

[0059] According to a preferred embodiment, the particle size ranges from 0.8 mm to 1.5 mm, preferably from 1 mm to 1.4 mm.

[0060] The following experimental section provides some details of the method of the present invention, which are for illustrative purposes only.

[0061] The granules of this invention allow for a prolonged release time of melatonin when ingested by an individual requiring melatonin. The granules can be used directly, for example, encapsulated in gelatin capsules, for the treatment of sleep disorders and for reducing the time required to fall asleep.

[0062] Preferably, the particles of the present invention can be used to prepare pharmaceutical compositions and dietary supplements containing controlled-release melatonin.

[0063] According to another aspect of the invention, an object of the invention is also to provide an oral pharmaceutical composition and / or dietary supplement comprising the particles of the invention, and one or more conventional excipients and / or carriers.

[0064] According to a preferred embodiment of the present invention, the composition of the present invention is in the form of gummy candy, chewable tablet, capsule or gum.

[0065] To prepare the preferred compositions of the present invention, the particles of the present invention can be mixed with excipients known to those skilled in the art for use in the manufacture of gummies, chewable tablets, capsules, or chewing gum. For example, sugars, including glucose syrup, modified starch, gelatin, pectin, water, and vegetable oils, can be used to prepare the gummies, and flavoring agents, coloring agents, and conventional coating agents can be added, for example.

[0066] Alternatively, the compositions of the present invention may be in the form of tablets, hard capsules, soft capsules, granules, fine granules, powders, tablets, syrups, emulsions, suspensions, and solutions suitable for oral administration. Other suitable pharmaceutical forms may also be used.

[0067] These compositions can be taken alone, for example, when in the form of gummies, chewable tablets or gum; or when in capsule form and taken with water; or, especially when in powder or granule form, can be mixed with other foods, such as yogurt, cream, gels, etc.

[0068] Alternatively, the compositions of the present invention may be in the form of ready-to-use beverages, such as drinking sachets, "strip packaging," in which case cream or gel is preferred.

[0069] In addition to what has already been mentioned, those skilled in the art can appropriately select the types of pharmaceutical and food additives used to prepare the compositions of the present invention, the content ratio of additives to active ingredients, and the methods for preparing pharmaceutical compositions or food supplements.

[0070] For conventional carriers and excipients, organic or inorganic substances, or solid or liquid substances, can be used, provided that they are edible, physiologically acceptable, and compatible with all other components of the composition.

[0071] As mentioned above, those skilled in the art are fully capable of selecting the most suitable carriers and excipients to prepare the composition.

[0072] For example, organic or inorganic substances, or solid or liquid substances, can be used as excipients and carriers, provided they are edible and pharmaceutically acceptable. Examples of excipients used in the preparation of solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, stearic acid or magnesium stearate, lactose, polyethylene glycol, mannitol, sorbitol, chelating agents, anti-caking agents, sweeteners, preservatives, and flavoring agents.

[0073] To prepare an orally administered liquid composition, conventional inert diluents, such as water or oil, such as vegetable oil, can be used. In addition to an inert diluent, the liquid composition may contain adjuvants such as wetting agents, suspending agents, sweeteners, flavoring agents, coloring agents, and preservatives. The liquid composition may be contained in capsules made of absorbable material, such as gelatin.

[0074] Sweeteners can be one or more natural sugars, optionally reducing sugars such as sucrose, glucose, xylitol, mannitol, or sorbitol, or synthetic products such as sodium saccharin, aspartame, acesulfame K, or sucralose. Acidulants may also be added.

[0075] Flavorings are pharmaceutically acceptable aromas and flavors derived from synthetic or natural oils, the latter being extracted from plants, flowers, fruits, and combinations thereof, such as cinnamon, peppermint, fennel, and citrus leaves, bitter almonds, citrus fruits (especially oranges and / or lemons), linden, vanilla, chocolate, and grapefruit oils. Chocolate, vanilla, or eucalyptus flavorings, as well as fruit flavorings, especially apple, pear, peach, strawberry, apricot, orange, lemon, and grape, may also be used advantageously.

[0076] The experimental section below provides examples of the compositions of the present invention for illustrative purposes only.

[0077] The compositions of the present invention may contain 0.5 mg to 10 mg of melatonin, preferably 1 mg to 3 mg of melatonin, for example 1 mg or 2 mg.

[0078] As will be shown in the experimental section, compositions containing the particles of the present invention, particularly in the form of gummies, exhibit dissolution profiles that are particularly suitable for treating sleep disorders, reducing the time required to fall asleep, and for maintaining a state of sleep.

[0079] The term “sleep disorder” as used herein is intended to include any pathology related to sleep, such as difficulty falling asleep, problems with sleep duration, sleep consolidation, or sleep quality; preferably, the term refers to primary insomnia.

[0080] The particles or compositions of the present invention are non-toxic and intended for use on mammals, preferably humans, and are suitable for any age group: from adolescents to the elderly.

[0081] The granules or compositions of the present invention should be administered shortly before bedtime, for example, 15 to 60 minutes beforehand, preferably 30 to 40 minutes beforehand. Typically, a melatonin dose of 1 mg to 3 mg (e.g., 1 mg or 2 mg) is sufficient to achieve the desired effect. However, these doses can vary depending on the age, sex, health condition, and severity of the disease of the person being treated.

[0082] According to another aspect of the invention, an object of the invention is to use the particles and compositions of the invention in the treatment of sleep disorders as defined above.

[0083] According to another aspect, the object of the present invention is to provide a method for treating the aforementioned sleep disorder, comprising administering an effective amount of the particles or composition of the present invention to a subject in need.

[0084] According to another aspect, the object of the present invention is to provide a combination of melatonin, sodium alginate and calcium lactate.

[0085] According to another aspect, the object of the present invention is a method for treating sleep disorders as defined above, using a combination of melatonin, sodium alginate and calcium lactate.

[0086] According to another aspect, the object of the present invention is to use a combination of melatonin, sodium alginate and calcium lactate as the active ingredient of a preferred sustained-release pharmaceutical composition in a method for treating sleep disorders as defined above.

[0087] According to another aspect, the object of the present invention is to use a combination of melatonin, sodium alginate and calcium lactate as the active ingredient of sustained-release granules in a method for treating sleep disorders as defined above.

[0088] The invention will now be described in more detail in the experimental section below, for illustrative purposes only and in no way limiting the invention.

[0089] Experimental Section

[0090] Example 1

[0091] Granulation process

[0092] Step (a)

[0093] Element weight% Melatonin with a titer of 99% 2.0％ Sodium alginate 49％ Calcium lactate 49％

[0094] Table 1 - Granulation in the Diosna mod. P1 / 6 laboratory

[0095] Add sodium alginate (e.g., about 49 wt%), melatonin (e.g., about 2 wt%), and calcium lactate pentahydrate (e.g., about 49 wt%) in sequence. Set the impeller to 200 rpm and pour in an appropriate amount of purified rinsing water. After adding, set the shredder to 1000 rpm and the impeller to 200 rpm for 5 minutes. Pass the wet particles through a 3 mm sieve.

[0096] Drying stage

[0097] The granules were dried in an oven at 60°C for 8 hours. LOD control = 6.3%.

[0098] Correction phase

[0099] Calibration is performed using a 1.2mm sieve.

[0100] Step (b)

[0101] Element weight% Particles from step (a) 98.12％ Sodium alginate 0.44％ Calcium lactate 1.44％

[0102] Table 2

[0103] Step (b')

[0104] Granulation was performed using Glatt Fluid Bed mod.Uniglatt.

[0105] Preparation of coating solution

[0106] Dissolve calcium lactate in an appropriate amount of purified water.

[0107] Coating stage

[0108] The particles obtained in step 1 are loaded into a fluidized bed basket. The coating solution is sprayed using the following parameters: inlet air temperature = 40°C to 45°C.

[0109] Product temperature = 27℃ to 30℃

[0110] Spraying pressure = 1.5 bar

[0111] Liquid flow rate = 15 g / min to 20 g / min

[0112] Airflow = Baffle position 15

[0113] After spraying the coating solution, dry the product by setting the following parameters. =

[0114] Inlet air temperature = 60℃ to 65℃

[0115] Product temperature = 50℃ to 55℃

[0116] Airflow = Baffle position 15

[0117] LOD control = 6.5% to 7.5%

[0118] Step (b)

[0119] Granulation was performed using Glatt Fluid Bed mod.Uniglatt.

[0120] Preparation of coating solution

[0121] Dissolve sodium alginate in water

[0122] Coating stage

[0123] The particles obtained from step (b') are loaded into a fluidized bed basket. The coating solution is sprayed by setting the following parameters: inlet air temperature = 40°C to 45°C.

[0124] Product temperature = 27℃ to 30℃

[0125] Spraying pressure = 1.5 bar

[0126] Liquid flow rate = 15 g / min to 20 g / min

[0127] Airflow = Baffle position 15

[0128] After spraying the coating solution, dry the product by setting the following parameters:

[0129] Inlet air temperature = 60℃ to 65℃

[0130] Product temperature = 50℃ to 55℃

[0131] Airflow = Baffle position 15

[0132] LOD control = 6.5% to 7.5%

[0133] Correction phase

[0134] The particles are corrected using a 1.2mm sieve.

[0135] Example 2

[0136] Granulation process

[0137] Step (a)

[0138] Element weight% Melatonin with a titer of 99% 10.0％ Sodium alginate 45％ Calcium lactate 45％

[0139] Table 3 - Granulation in Glatt Fluid Bed mod. Unigratt

[0140] In this case, a single-step granulation step is performed in a Glatt fluidized bed using all components and 40% purified water.

[0141] Coating stage

[0142] Melatonin (e.g., about 10% by weight), sodium alginate (e.g., about 45% by weight), and calcium lactate (e.g., about 45% by weight) are loaded into a fluidized bed basket. Purified water is sprayed by setting the following parameters:

[0143] Inlet air temperature = 40℃ to 45℃

[0144] Product temperature = 27℃ to 30℃

[0145] Spraying pressure = 1.5 bar

[0146] Liquid flow rate = 15 g / min to 20 g / min

[0147] Airflow = Baffle position 15

[0148] After spraying purified water, dry the product by setting the following parameters:

[0149] Inlet air temperature = 60℃ to 65℃

[0150] Product temperature = 50℃ to 55℃

[0151] Airflow = Baffle position 15

[0152] LOD control = 6.5% to 7.5%

[0153] Correction phase

[0154] The particles are corrected using a 1.2mm sieve.

[0155] The resulting granules have the following specifications:

[0156] Particle size:

[0157] Not exceeding 10%: ≥710μm

[0158] 80% are between 125μm and 710μm

[0159] Not exceeding 10%: <125μm

[0160] LOD (70℃): 6.0% to 8.0%

[0161] Density: 0.4 g / ml to 0.6 g / ml

[0162] Flowability (100g): ≤25 seconds

[0163] Example 3

[0164] The composition of the present invention is prepared in the form of gummy candy.

[0165] Mold form: "menthol boluses"

[0166] Weight of a single candy: approximately 2g

[0167] Element:

[0168] The granules obtained from Example 1, glucose syrup, sugar, modified starch, water, vegetable oil (coconut oil, rapeseed oil), flavoring agent, coloring agent: E133, coating agent: carnauba wax.

[0169] Example 4

[0170] Dissolution test

[0171] Example 4.1

[0172] According to the USP dissolution test (500 mL 0.1 N HCl, 37 °C, 100 rpm)

[0173] time Divide the candy from Example 3 into two portions. Cut the candy from Example 3 into small pieces. 30 minutes 19.3％ 29.6％ 2 hours 40.0％ 71.6％ 4 hours 54.7％ 76.2％

[0174] Table 4

[0175] Example 4.2

[0176] Dissolution test (900 mL pH 7 buffer, 37°C, 100 rpm)

[0177] time Divide the candy from Example 3 into two portions. Cut the candy from Example 3 into small pieces. 30 minutes 29.8％ 41.3％ 2 hours 57.0％ 55.6％ 4 hours 63.2％ 71.1％

[0178] Table 5

[0179] Experimental Section

[0180] Alginate is a naturally occurring linear copolymer extracted from the cell walls of brown algae in the genera *Laminaria* and *Ascophillum*. Alginate from algae must undergo a series of processing steps before it can be practically used in applications requiring high purification. Because alginate from algae is insoluble, it needs to be converted into soluble sodium alginate.

[0181] Alginate has attracted widespread attention for its applications, primarily because it can react with divalent cations (such as Ca2+). 2+ In the presence of alginate, it forms a polymeric gel. The interest in the application of alginate stems primarily from its ability to form gels, making the study of the gelation process crucial.

[0182] A gel is a solid composed of a three-dimensional molecular network, where molecules are linked by connective regions (physical or chemical properties) to form a solid phase within which a dispersed liquid medium is embedded. The network imparts the properties of the gel solid, while the liquid phase controls its density. In solutions containing divalent cations, these polymers induce ionic bonds between different polymer chains, promoting the sol-gel transition.

[0183] Ca 2+ The cations first bind to the G groups until the available binding sites are saturated. Next, they continue to bind to the M groups, which consist of monomeric units of mannuronic acid (at least at the macroscopic level, especially when adjacent units consist of G residues), until chain binding is restricted by the network. This observation can be explained by the interaction of the M and G blocks with Ca... 2+ The cations differ in their ability to form linker regions. The latter are all polyanions and will form intermolecular anionic bonds with divalent cations. However, due to the spatial organization of the G block, they can also chelate Ca. 2+This allows it to form binding sites between two adjacent G blocks, resulting in stronger interactions. Consequently, dimerization occurs rather than aggregation. This led to the development of the "egg-box" model, named after the characteristic shape of the molecular structure created.

[0184] In addition, relative alginate affinity rankings were established for several divalent cations of interest:

[0185] Pb 2+ >Cu 2+ >Cd 2+ >Ba 2+ >Sr 2+ >Ca 2+ >Co 2+ =Ni 2+ =Zn 2+ >Mn 2+ >Mg 2+

[0186] Of all possible divalent cations, Ca was chosen considering both affinity and safety. 2+ .

[0187] One of the main problems when using alginate gels is their low chemical stability.

[0188] Substances with high affinity for them (such as phosphates or citrates) can chelate calcium ions, making the initial gel unstable. The gel may also be unstable due to the presence of other non-gelling cations.

[0189] Therefore, the choice of calcium lactate did not seem obvious, but rather the result of careful selection, taking into account the chemical and physical properties of calcium lactate itself as well as other components present in the granule composition (sodium alginate and melatonin).

[0190] Of all possible calcium salts, calcium lactate was chosen because of the following properties that make it the preferred salt for preparing melatonin granules:

[0191] - Good water solubility;

[0192] -5% calcium lactate aqueous solution pH value: 6-8;

[0193] - Calcium titer: 13.4% to 14.5%.

[0194] Other possible calcium salts were ruled out because they are insoluble in water (e.g., calcium carbonate) or have poor solubility (e.g., calcium citrate), or although soluble, their pH is incompatible with the other two components (melatonin and sodium alginate) in the granular composition once dissolved in water.

[0195] Alternatively, you can choose lactic acid and safety with Ca. 2+ Equivalent divalent cation (i.e., Mg) 2+ The salt formed by lactic acid and the divalent cation Mg. 2+ The resulting salt is magnesium lactate. Magnesium lactate is very similar to calcium lactate in its chemical and physical properties.

[0196] - Good water solubility;

[0197] -5% magnesium lactate aqueous solution pH: 6.5 to 8.5;

[0198] -Mg titer: 10.0% to 10.5%.

[0199] However, although magnesium lactate is similar to calcium lactate in chemical and physical properties, it is not considered a viable candidate. The efficacy of magnesium lactate in sustained-release granules (including those containing melatonin and sodium alginate) is not considered equivalent to that of calcium lactate because Mg... 2+ Ions do not possess gelling properties, while Ca... 2+ Ions possess [the following characteristics].

[0200] To provide experimental evidence, granules were prepared using magnesium lactate in a 1:1 ratio instead of calcium lactate. The tested compositions, the granulation process used, and the test results are given below:

[0201]

[0202] Single-step granulation was performed using all ingredients and 40% by weight of purified water.

[0203] Coating stage

[0204] Melatonin (e.g., about 10% by weight), sodium alginate (e.g., 45% by weight), and magnesium lactate (e.g., 45% by weight) are loaded into a fluidized bed basket.

[0205] Spray purified water by setting the following parameters:

[0206] Inlet air temperature = 40℃ to 45℃

[0207] Product temperature = 27℃ to 30℃

[0208] Spraying pressure = 1.5 bar

[0209] Liquid flow rate = 15 g / min to 20 g / min

[0210] Airflow = Baffle position 15

[0211] After completing the wetting stage with purified water, drying is performed by setting the following parameters:

[0212] Inlet air temperature = 60℃ to 65℃

[0213] Product temperature = 50℃ to 55℃

[0214] Airflow = Baffle position 15

[0215] LOD control = 6.5% to 7.5%

[0216] Correction phase

[0217] The particles are corrected using a 1.2mm sieve.

[0218] The resulting granules have the following specifications:

[0219] Particle size:

[0220] Not exceeding 10%: ≥710μm

[0221] 80% are between 125μm and 710μm

[0222] Not exceeding 10%: <125μm

[0223] LOD (70℃): 6.0% to 8.0%

[0224] Density: 0.45 g / ml to 0.65 g / ml

[0225] Flowability (100g): ≤25 seconds

[0226] The particles obtained using magnesium lactate have overlapping chemical and physical properties with those obtained using calcium lactate.

[0227] To test the gelling properties of the magnesium lactate-containing particles, which is the reason for the melatonin granules' function, 1 gram of calcium lactate-containing particles and 1 gram of magnesium lactate-containing particles were poured into 150 mL of 0.1 N HCl solution to simulate the gastric environment.

[0228] Figure 1 and Figure 2A , 2B A photo showing the test results:

[0229] Figure 1 (The left side shows particles containing magnesium lactate, and the right side shows particles containing calcium lactate) This shows the behavior of the two types of particles just after being poured into 0.1N HCl.

[0230] Figure 2A and 2B The diagram shows the behavior of two types of particles immediately after being poured into 0.1N HCl (top view). The particles on the left contain magnesium lactate, and the particles on the right contain calcium lactate.

[0231] As can be seen from the photos, melatonin particles containing calcium lactate hydrate uniformly upon contact with 0.1N HCl solution, resulting in smooth and uniform gelation of the powder particles without forming aggregates. On the other hand, particles containing magnesium lactate are difficult to hydrate, require a longer hydration time, and tend to form large aggregates. The gel formed by its hydrated portion has irregular characteristics, making it unsuitable for forming a gel layer around the powder particles.

Claims

1. A sustained-release particle comprising or consisting of melatonin, sodium alginate and calcium lactate.

2. The particle according to claim 1, wherein The particles contain: 1 wt% to 20 wt% of melatonin, preferably 1.5 wt% to 15 wt%, more preferably 2 wt% to 10 wt%, relative to the total weight of the particles; 20 wt% to 60 wt% of sodium alginate, preferably 40 wt% to 55 wt%, more preferably 45 wt% to 50 wt%, relative to the total weight of the particles; and 30 wt% to 60 wt% of calcium lactate, preferably 40 wt% to 55 wt%, more preferably 45 wt% to 50 wt%, relative to the total weight of the particles.

3. A method for preparing the particles according to claim 1 or 2, wherein: The method comprises the following steps: a. wet granulation of a mixture comprising melatonin, sodium alginate and calcium lactate or consisting of melatonin, sodium alginate and calcium lactate to form particles to be coated; b. The granules obtained by step (a) are coated by the following two consecutive steps: b' granulating the granules obtained in step (a) with calcium lactate; and b" granulates the particles obtained in step (b') with sodium alginate.

4. A method for preparing the particles according to claim 1 or 2, wherein: The method comprises granulating a mixture comprising or consisting of melatonin, sodium alginate and calcium lactate, and then coating the mixture with a mixture comprising or consisting of sodium alginate and calcium lactate.

5. A combination consisting of melatonin, sodium alginate and calcium lactate.

6. A pharmaceutical and / or food composition comprising the particles according to claim 1 or 2, or the combination according to claim 5, and one or more conventional excipients and / or carriers.

7. The composition according to claim 6, characterized in that It is in the form of an oral composition.

8. The composition according to claim 7, characterized in that It comes in the form of a soft candy, chewable tablet, capsule, or gum.

9. The composition according to any one of claims 6 to 8, characterized in that It contains 0.5 mg to 5 mg of melatonin, preferably 1 mg to 3 mg of melatonin.

10. The particles of claim 1 or 2, the composition of claim 5, or the composition of any one of claims 6 to 9, for use in a method for treating sleep disorders, preferably primary insomnia, for reducing the time required to fall asleep and for maintaining a sleeping state.

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