Sustained-Release Melatonin Compositions

Abstract

The present invention relates to compositions comprising melatonin encapsulated within a calcium alginate hydrogel. The invention also provides orally administrable dosage forms comprising such compositions retained within a gel, the gel being formed using starch as a gelling agent. Methods for making these compositions and their use in therapy are also disclosed.

Description

[Technical Field]

[0001] The present invention relates to melatonin compositions useful in preparing orally administrable gelled dosage forms that provide sustained release of melatonin upon ingestion. [Background technology]

[0002] Melatonin, (N-acetyl-5-methoxytryptamine; CAS: 73-31-4C 13 H 16 N2O2 (molecular weight: 232.3) is the major hormone secreted by the pineal gland in vertebrates. Endogenous melatonin is known to function in regulating the sleep-wake cycle (circadian rhythm), pubertal development, and seasonal adaptation, and its mechanism of action is being elucidated. Physiological concentrations of melatonin are approximately 10 pg / mL during the day and increase to approximately 100 pg / mL at night. Melatonin concentrations have also been found to change with age. Peak melatonin secretion occurs around 2:00 AM.

[0003] The therapeutic use of exogenous melatonin has also been well studied. RJ Reiter et al., Curr. Med. Chem. 2010, 17(19), 2070-2095, reviewed the clinical use of melatonin in human trials. In particular, melatonin has found applications in macular degeneration, glaucoma, gastric mucosal protection, irritable bowel syndrome, arterial hypertension, diabetes, chemotherapy and radiation side effects in cancer patients, and hemodialysis in patients with renal failure. It has also found applications as adjuvant therapy for sleep disorders of circadian etiology (e.g., jet lag, delayed sleep phase syndrome, and age-related sleep deterioration), as well as conditions associated with neurodegenerative diseases (e.g., Alzheimer's disease) or Smith-Magenis syndrome. Melatonin has been used at doses ranging from 0.1 mg to 300 mg, and has been observed to be low in toxicity and non-addictive.

[0004] The most notable therapeutic use of melatonin is for the treatment of sleep disorders. Melatonin helps maintain sleep and speeds sleep onset, making it one of the most frequently requested over-the-counter sleep aids. N. Covasin et al., JAMA. 2022, 327(5), 483-485, and colleagues reported a five-fold increase in melatonin supplement use among US adults (n=55,021, mean age 47.5 [SD 17.1] years; 52% women) from 1999-2000 (0.4%) to 2017-2018 (2.1%).

[0005] As evidence of its widespread use, melatonin is available in a variety of dosage forms, including liquid, tablet, capsule, and gummy formulations. An exemplary gummy formulation is Natrol® 10 mg Melatonin Gummies, a dietary supplement that helps people fall asleep faster and stay asleep longer. Natrol® Melatonin Gummies are non-GMO, vegan, and gluten-free, gelatin-free, and free of artificial colors, flavors, sweeteners, and preservatives. Similarly, Nature's Bounty® immediate-release melatonin products include Sleep Gummies, which contain 3 mg of melatonin and 200 mg of L-theanine per serving. Other ingredients include corn syrup, sugar, gelatin, succinic acid, fractionated coconut oil (containing carnauba wax), natural flavors, pectin, and vegetable and fruit juices (for color).

[0006] However, despite the availability of numerous compositions, many challenges remain with administering exogenous melatonin. First, melatonin has demonstrated poor and highly variable bioavailability. This variability is due to a short half-life of 20-50 minutes, high first-pass metabolism in the liver, and / or poor intestinal absorption. Furthermore, melatonin plasma concentrations can take more than 30 minutes to reach their peak. In some cases, melatonin must be administered up to two hours before bedtime. As a result, low doses of 0.1-1 mg, which correspond to physiological plasma concentrations, are much less effective than higher doses. However, higher doses are less desirable, at least due to the persistence of melatonin in the blood after awakening, when physiological concentrations should be significantly lower.

[0007] Solutions to these challenges have focused on innovative methods for sustained release of melatonin during nighttime sleep. This approach maintains peak plasma concentrations for a longer period of time, which in turn leads to improved sleep quality (reduced sleep disturbances). For this reason, sustained-release melatonin supplements are considered superior to immediate-release supplements.

[0008] CIRCADIN® (disclosed in U.S. Pat. No. 6,469,044), manufactured by Neurim Pharmaceuticals, is a 2 mg sustained-release melatonin tablet for treating insomnia in patients over 55 years of age. The component responsible for the sustained-release profile is an acrylic resin carrier (EUDRAGIT® RS 100, ammonio methacrylate copolymer type B), which reduces the dissolution rate of melatonin. However, WO 2018 / 078429 discloses compliance issues among patients taking CIRCADIN® due to the large tablets (8.1 mm diameter and 3-5 mm thick) being difficult to swallow. Circadin® tablets, when broken, crushed, or chewed by patients, exhibit a release profile similar to that of immediate-release melatonin.

[0009] SLYENTO® is indicated for the treatment of insomnia in children and adolescents aged 2 to 18 years with autism spectrum disorder (ASD) and / or Smith-Magenis syndrome. Tablets contain 1 mg or 5 mg of melatonin and are administered with an acrylic resin carrier (ammonio methacrylate copolymer type A / B) for a sustained-release profile.

[0010] WO 2020 / 150605 discloses tablet and capsule dosage forms containing a solid micronized melatonin composition. The granulated melatonin contains a carboxylic acid and a hydrogel-forming polymer, which provide a sustained-release profile upon ingestion. However, the inventors report that the dosage form must be prepared by dry granulation, avoiding wet granulation methods. This is because water causes deamination of the melatonin, reducing the content uniformity of the dosage form.

[0011] WO 2012 / 103411 describes a multi-layered sustained release melatonin tablet, where the sustained release layer comprises a material capable of forming a hydrogel.

[0012] Although gummy formulations are a preferred dosage form for exogenous melatonin, research on sustained-release gummies is limited. The primary reason is that developing sustained-release gummies poses significant challenges compared to their tablet counterparts. For example, existing technologies for sustained-release melatonin tablets rely on layered structures, but this approach is unsuitable for gummies. Furthermore, gummies are prepared at high temperatures using high shear forces, and these harsh conditions adversely affect the stability of sustained-release forms of melatonin.

[0013] To the inventors' knowledge, there are only two prior disclosures of sustained-release melatonin gummies. WO 2021 / 144403 discloses a hydroxypropyl methylcellulose (HPMC) gummy formulation containing melatonin pellets formed by spray-coating microcrystalline cellulose (MCC) spheres with micronized melatonin dispersed in a 10% aqueous solution of HPMC. One limitation of this approach is that HPMC is a cellulose-based coating known to dissolve at approximately 65°C. Therefore, given that the heating step in gummy preparation can exceed 90°C, these sustained-release melatonin pellets are limited to very limited gummy manufacturing processes. NiteThru® Two-Stage Release Gummies from Strides Consumer LLC contain 6 mg of melatonin in two forms: as an immediate-release formulation and also as sustained-release encapsulated melatonin. Other ingredients include corn syrup, sucrose, stevia, purified water, pectin, carrageenan, gellan gum, citric acid, sodium citrate, strawberry flavor, natural color (E163), carnauba wax, microcrystalline cellulose, polyvinyl acetate, basic methacrylate copolymer, and stearic acid. However, consumers have raised concerns that the carrageenan present in some gummy compositions is harmful to human health.

[0014] Therefore, there remains a need to provide improved sustained release melatonin gummies to maintain peak plasma concentrations of melatonin for longer periods of time, thus improving the quality of sleep rest. [Summary of the Invention]

[0015] In a first embodiment, the present invention provides a composition comprising melatonin encapsulated within a calcium alginate hydrogel.

[0016] In a second embodiment, the present invention provides an orally administrable dosage form comprising a composition according to the first embodiment held within a gel, wherein the gel is formed using starch as a gelling agent.

[0017] In a third embodiment, the present invention provides a method for preparing a composition comprising melatonin encapsulated within a calcium alginate hydrogel.

[0018] In a fourth embodiment, the present invention provides a method for preparing one or more orally administrable dosage forms comprising a composition according to the first embodiment held within a gel, wherein the gel is formed using starch as a gelling agent.

[0019] In a fifth embodiment, the present invention provides a composition according to the first embodiment, or an orally administrable dosage form according to the second embodiment, for use in the treatment of a sleep disorder.

[0020] In a sixth embodiment, the present invention provides the use of a composition according to the first embodiment in the manufacture of a medicament, such as an orally administrable dosage form according to the second embodiment, for the treatment of a sleep disorder.

[0021] In a seventh embodiment, the present invention provides a method of treating a sleep disorder in an individual in need thereof, comprising administering to the individual a composition according to the first embodiment or an orally administrable dosage form according to the second embodiment. [Brief explanation of the drawings]

[0022] Examples of the present invention will now be described in detail with reference to the accompanying drawings. [Figure 1]FIG. 1 shows a schematic diagram of a composition comprising melatonin encapsulated within a calcium alginate hydrogel. [Figure 2] 1 shows the % melatonin released over time in simulated gastric fluid, comparing compositions of the present invention with prior art Natrol® and NiteThru® products. DETAILED DESCRIPTION OF THE INVENTION

[0023] In a first embodiment, the present invention provides a composition comprising melatonin encapsulated within a calcium alginate hydrogel. The inventors have discovered that such a composition provides sustained release of melatonin upon ingestion and is resistant to the harsh conditions used to manufacture gummy formulations, a preferred dosage form for this particular active ingredient. Preferably, the weight ratio of melatonin to calcium alginate hydrogel in the composition is 5:95 to 15:85, more preferably about 10:90. The composition preferably contains 4 to 10% by weight of water, more preferably 6 to 8% by weight of water, based on the total weight of the composition. The composition may further contain sodium ions and lactate ions.

[0024] In a second embodiment, the present invention provides an orally administrable dosage form comprising a composition according to the first embodiment held within a gel, wherein the gel is formed using starch as a gelling agent. Gelled dosage forms are often referred to as gummy formulations, and the inventors have discovered that the use of starch as a gelling agent is essential to the successful preparation of gummy formulations that use a composition comprising melatonin encapsulated within a calcium alginate hydrogel as the sustained release component.

[0025] Preferably, the dosage form comprises 1-3 wt. % of the composition according to the first embodiment, based on the total weight of the dosage form. In a further preferred embodiment, the dosage form comprises melatonin not encapsulated in a calcium alginate hydrogel. This melatonin is included to provide immediate release of the active ingredient upon ingestion, while melatonin encapsulated in a calcium alginate hydrogel is included to provide sustained release of the active ingredient overnight. Preferably, the dosage form comprises 0.01-0.03 wt. % of melatonin not encapsulated in a calcium alginate hydrogel, based on the total weight of the dosage form.

[0026] Although different forms of starch can be used, the gel is preferably formed using potato starch as the gelling agent. A suitable commercially available potato starch is Perfectamyl Gel NF. Preferably, the final dosage form contains 7-17 wt.% starch, based on the total weight of the dosage form. Additionally, the dosage form may contain 8-18 wt.% water, based on the total weight of the dosage form.

[0027] In a preferred embodiment, the dosage form further comprises one or more sweeteners, preferably in an amount of 52-82% by weight based on the total weight of the dosage form. The one or more sweeteners are preferably selected from the group consisting of sucrose and corn syrup, and are preferably sucrose, 53-73 DE corn syrup, and 32-52 DE corn syrup. In a more preferred embodiment, the dosage form comprises 26-36% by weight of sucrose, 18-28% by weight of 53-73 DE corn syrup, and 8-18% by weight of 32-52 DE corn syrup, based on the total weight of the dosage form. The 53-73 DE corn syrup is preferably about 63 DE corn syrup (e.g., Globe 63 DE Corn Syrup). The 32-42 DE corn syrup is preferably about 42 DE corn syrup (e.g., Globe 42 DE Corn Syrup).

[0028] The dosage form also preferably contains one or more acidulants, preferably in an amount of 0.6 to 1.2% by weight based on the total weight of the dosage form. A preferred acidulant is citric acid. The dosage form also preferably contains L-theanine, preferably in an amount of 2 to 4% by weight based on the total weight of the dosage form. The dosage form also preferably contains one or more natural flavors (e.g., natural blueberry flavor WONF (WS-320-249-8) and / or natural bitterness masking binder flavor (TV-785-446-1)) and / or natural colorants (e.g., fruit juice such as grape juice, of which FruitMaxPurple 1302 WS is a commercially available example). The dosage form also preferably contains a glazing agent (e.g., vegetable oil and / or carnauba wax, of which Capol 42-3073 A MB is a commercially available example).

[0029] The orally administrable dosage forms of the present invention provide sustained release of melatonin over an extended period of time, and optionally also provide immediate release of melatonin. The combination of both immediate and sustained release melatonin provides overnight exposure and provides a more effective treatment for sleep disorders.

[0030] In a third embodiment, the present invention provides a method for preparing a composition comprising melatonin encapsulated in a calcium alginate hydrogel, comprising: i) forming a preblend of melatonin, a calcium ion source, and an alginate source; ii) granulating the preblend by wet granulation to form granules of a composition comprising melatonin encapsulated in a calcium alginate hydrogel; and iii) drying the granules to a moisture content of less than 15% by weight based on the total weight of the granules.

[0031] Preferably, the calcium ion source is calcium lactate and / or the alginate source is sodium alginate. Preferably, the wet granulation step ii) comprises spraying water at a rate of 500-1000 mL / min. Preferably, the drying step iii) comprises drying the granules to a moisture content of 6-8 wt. % based on the total weight of the granules.

[0032] In a fourth embodiment, the present invention provides a method for preparing one or more orally administrable dosage forms comprising a composition comprising melatonin encapsulated within a calcium alginate hydrogel, comprising: i) providing a mixture comprising starch and water; ii) heating the mixture from step i) with high shear mixing to prepare the starch for gelatinization; iii) cooling the mixture from step ii); iv) combining the product of step iii) with a composition comprising melatonin encapsulated in a calcium alginate hydrogel; v) transferring the product of step iv) into one or more molds of a size and shape suitable for an orally administrable dosage form; vi) curing and drying the transferred product of step iv) to provide one or more orally administrable dosage forms comprising a composition (e.g., any composition disclosed herein) retained within a gel.

[0033] Preferably, the mixture of step i) comprises starch and water in a weight ratio of 35:65 to 55:45, preferably 40:60 to 50:50, more preferably about 45:55. Preferably, the mixture of step i) further comprises one or more sweeteners. Preferably, the heating of step ii) is at a temperature of 140-160°C under a pressure of 1-5 bar. Preferably, the heating of step ii) is by direct steam injection. Preferably, during step iv), the product of step iii) is also combined with an acidulant and / or melatonin and / or L-theanine and / or natural flavors and / or natural colors that are not encapsulated in a calcium alginate hydrogel.

[0034] Preferably, one or more products of step vi) are coated with a polishing agent.

[0035] As mentioned above, the therapeutic use of melatonin for the treatment of sleep disorders is known. Accordingly, in a fifth embodiment, the present invention further provides a composition comprising melatonin encapsulated in a calcium alginate hydrogel, or an orally administrable dosage form comprising a composition comprising melatonin encapsulated in a calcium alginate hydrogel, for use in the treatment of sleep disorders.

[0036] In a sixth embodiment, the present invention provides the use of a composition according to the first embodiment in the manufacture of a medicament, such as an orally administrable dosage form according to the second embodiment, for the treatment of a sleep disorder.

[0037] In a seventh embodiment, the present invention provides a method of treating a sleep disorder in an individual in need thereof, comprising administering to the individual a composition according to the first embodiment or an orally administrable dosage form according to the second embodiment.

[0038] "Sustained release" melatonin is also known to those skilled in the art as slow release melatonin, continuous release melatonin, time release melatonin, prolonged release melatonin, and controlled release melatonin. The sustained release melatonin in various embodiments disclosed herein is melatonin encapsulated within a calcium alginate hydrogel. "Immediate release" melatonin, also known to those skilled in the art as "quick release" melatonin, is optionally present in any of the embodiments disclosed herein and is not encapsulated by a calcium alginate hydrogel, and preferably is not encapsulated by any form of alginate.

[0039] In particularly preferred embodiments of the first through seventh embodiments described above, oral administration of any of the orally administrable dosage forms disclosed herein results in all of the following three effects: (i) faster sleep onset (i.e., reduced sleep delay), (ii) longer sleep duration (i.e., increased time from sleep to awakening), and (iii) increased relaxation, sedation, and / or tranquility, all relative to an individual ingesting an otherwise identically formulated comparison product lacking melatonin and optional L-theanine.

[0040] In some embodiments, a single nighttime dose of any of the orally administrable dosage forms disclosed herein is administered. In such embodiments, the single nighttime dose can be administered as one discrete unit of the dosage form or as multiple discrete units of the dosage form, preferably about 30 minutes before bedtime (e.g., 15-45 minutes before bedtime). As a specific, non-limiting example, two units of the orally administrable dosage form (e.g., two gummies) can be administered as a single dose containing a predetermined amount of melatonin, for example, about 10 mg total melatonin per dose (e.g., 5-15 mg total melatonin per dose). Preferably, a single nighttime dose is administered to an individual (e.g., an individual experiencing temporary insomnia) containing (i) an amount of immediate-release melatonin effective to help the individual fall asleep more quickly, (ii) an amount of time-release melatonin effective to increase the amount of continuous sleep the individual receives, and (iii) optionally, an amount of L-theanine effective to at least one of relax, sedate, or calm the individual (e.g., about 100 mg of L-theanine per dose, e.g., 50-150 mg of L-theanine per dose).

[0041] In some embodiments, the orally administrable dosage form has one or more characteristics selected from the group consisting of: suitable for vegans, no artificial flavors, no artificial sweeteners, dairy-free, lactose-free, soy-free, gluten-free, wheat-free, fish-free, and 10 mg or less sodium (e.g., no sodium). Preferably, the orally administrable dosage form has all of these characteristics. [Example]

[0042] Example 1 Preparation of Sustained-Release Melatonin Granules Examples of compositions and methods for the industrial-scale preparation of sustained-release melatonin granules are provided below.

[0043] method The raw materials, calcium lactate, melatonin, and sodium alginate, were sieved and blended in a low-speed blender until homogenous. The resulting preblend was transferred to a fluidized-bed dryer, and the amount of purified water listed below was added to the dissolutor. Melatonin granules were then formed by wet granulation, in which water was sprayed onto the preblend at a rate of 500-2000 mL / min while shaking. A drying process was then carried out by setting the inlet air temperature within the range of 60-80°C, resulting in granules with a moisture content within the range of 6-8%. A cooling process was then carried out by setting the inlet air temperature at 20°C, resulting in a product temperature below 35°C.

[0044] [Table 1]

[0045] [Table 2]

[0046] Example 2 Preparation of sustained-release melatonin gummies Exemplary compositions and methods for the commercial-scale preparation of sustained-release gummies are provided below.

[0047] method Add preheated water (120 ml) to the premix weigher. o F (153 lb) and potato starch (perfectamyl gel, 185 lb) were added and mixed at 50% mixing speed until homogeneous. This was followed by the addition of 42DE corn syrup (205 lb) and the mixing speed was increased to 60% until homogeneous. Next, 63DE corn syrup (267 lb) was added and the mixing speed was increased to 70% until homogeneous. Finally, granulated sugar (490 lb) was added and the mixing speed was maintained at 70% until homogeneous.

[0048] The resulting premix slurry was then transferred to a buffer vessel using vacuum before being pumped through a jet cooker (149°C, 3.5 bar back pressure). A pressure dissolver with direct steam injection and high shear mixing was used to open the starch granules for gelatinization.

[0049] After the jet cooker, the heated mass is stored in a holding tank (190-210 o The mass is held in a buffer solution (pH = 5.5-6.5) and then pumped back into the buffer vessel, which is used to rapidly cool the mass and reduce the water content by evaporation.

[0050] In a separate tank, cold water (3.3 lb) was combined with 63DE corn syrup (9 lb) while stirring at 50% mixing speed for 45 seconds. This was followed by the addition of 50% w / w aqueous citric acid solution (2.7 lb) and stirring at the same speed for an additional 30 seconds. Melatonin (3.03 lb) was then added and stirred at 50% mixing speed for 60 seconds. The sustained-release melatonin granules of Example 1 (0.03 lb) were added and stirred at 60% mixing speed for 2-3 minutes. Finally, L-threonine (4.68 lb) was added and stirred at 60% mixing speed for 30 seconds.

[0051] The cooked mass was then pumped into an additive blending system where a portion (124.34 lb) was mixed with a mixture containing melatonin (22.74 lb), natural blueberry flavor (1.13 lb), natural bitterness masking agent (0.30 lb), and purple color mixture (1.50 lb).

[0052] After this final mixing step, the mass is transferred to a depositor hopper and dumped into a starch-filled tray for forming into gummies (3.75 g wet weight, pH 3.7-3.9). The gummies are then cooled to 125-145°C. o Place in a curing / drying chamber at a temperature of F and 8-20% RH for 20-60 hours to a dry gummies weight of 3.45 g. The gummies are then removed from the molds by hand and coated with a polish (Capol 42-3073 A MB).

[0053] Composition of sustained-release melatonin gummies (final product) The final dry gummy weight is 3.45g (range can be 2g-5g).

[0054] [Table 3]

[0055] Example 3 Bioavailability Testing of Sustained-Release Melatonin Gummies method Three melatonin gummies (processed to mimic chewing) were tested according to USP <2040> In a modified assay based on the method, the formulations were subjected to in vitro dissolution in simulated gastric fluid (0.1 N HCl at 37° C.) The formulations included commercially available Natrol® 10 mg and NiteThru® products, and a gummy formulation according to the present invention (labeled #1 Sleep 3 Gummies (without botanicals)).

[0056] result The melatonin dissolution profiles for these three formulations are shown below in Figure 2. It can be seen that the Natrol® 10 mg product provides a rapid, unsustained release of melatonin, whereas the NiteThru® product and the formulation according to the present invention provide a sustained release profile.

[0057] Example 4 Non-limiting examples of melatonin gummies

[0058] [Table 4]

[0059] Other Ingredients: Glucose syrup, sugar, modified food starch. Contains less than 2% of: citric acid, natural flavors, fruit and vegetable juices (color), vegetable oil (contains carnauba wax).

[0060] Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite articles "a" or "an" do not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

Claims

1. 1. A composition comprising melatonin encapsulated within a calcium alginate hydrogel, and optionally further comprising additional melatonin that is not encapsulated by calcium.

2. 2. The composition of claim 1, wherein the weight ratio of melatonin to calcium alginate hydrogel is from 5:95 to 15:

85.

3. 3. The composition of claim 2, wherein the weight ratio of melatonin to calcium alginate hydrogel is about 10:

90.

4. The composition of any one of claims 1 to 3, comprising 4 to 10 wt% water, based on the total weight of the composition.

5. The composition of claim 4, comprising 6 to 8 wt. % water, based on the total weight of the composition.

6. The composition of any one of claims 1 to 5, further comprising sodium ions and lactate ions.

7. 7. An orally administrable dosage form comprising the composition of any one of claims 1 to 6 held within a gel, wherein the gel is formed using starch as a gelling agent.

8. 8. The dosage form of claim 7, comprising 1 to 3% by weight of the composition of any one of claims 1 to 6, based on the total weight of the dosage form.

9. 9. The dosage form of claim 7 or claim 8, further comprising melatonin that is not encapsulated within the calcium alginate hydrogel.

10. 10. The dosage form of claim 9, comprising 0.01 to 0.03% by weight of melatonin not encapsulated within the calcium alginate hydrogel, based on the total weight of the dosage form.

11. 11. The dosage form of any one of claims 7 to 10, wherein the gel is formed using potato starch as a gelling agent.

12. 12. A dosage form according to any one of claims 7 to 11, comprising 7 to 17% by weight of starch, based on the total weight of the dosage form.

13. 13. The dosage form of any one of claims 7 to 12, comprising 8 to 18% by weight of water, based on the total weight of the dosage form.

14. 14. The dosage form of any one of claims 7 to 13, further comprising one or more sweeteners.

15. 15. The dosage form of claim 14, comprising 52 to 82% by weight of said one or more sweeteners, based on the total weight of the dosage form.

16. 16. The dosage form of claim 14 or claim 15, wherein the one or more sweeteners are selected from the group consisting of sucrose and corn syrup.

17. 17. The dosage form of claim 16, wherein the sweetener is sucrose, 53-73 DE corn syrup, and 32-52 DE corn syrup.

18. 18. The dosage form of claim 17, comprising 26-36% by weight sucrose, 18-28% by weight 53-73 DE corn syrup, and 8-18% by weight 32-52 DE corn syrup, based on the total weight of the dosage form.

19. 19. The dosage form of any one of claims 7 to 18, further comprising one or more acidulants.

20. 20. The dosage form of claim 19, comprising 0.6 to 1.2 wt. % of said one or more acidulants, based on the total weight of the dosage form.

21. 21. The dosage form of claim 19 or claim 20, wherein the one or more acidulants comprises citric acid.

22. 22. The dosage form of any one of claims 7 to 21, further comprising L-theanine.

23. 23. The dosage form of claim 22, comprising 2-4% by weight of L-theanine, based on the total weight of the dosage form.

24. 24. The dosage form of any one of claims 7 to 23, further comprising one or more natural flavors and / or natural colors.

25. 25. The dosage form of any one of claims 7 to 24, further comprising a glazing agent.

26. 1. A method for preparing a composition comprising melatonin encapsulated in a calcium alginate hydrogel, said method comprising: iv) forming a preblend of melatonin, a calcium ion source, and an alginate source; v) granulating the preblend by wet granulation to form granules of a composition comprising melatonin encapsulated in a calcium alginate hydrogel; vi) drying the granules to a moisture content of less than 15% by weight based on the total weight of the granules.

27. 27. The method of claim 26, wherein the calcium ion source is calcium lactate and / or the alginate source is sodium alginate.

28. 28. The method of claim 26 or claim 27, wherein the wet granulation comprises spraying water at a rate of 500 to 2000 mL / min.

29. 29. The method of any one of claims 26 to 28, wherein the granules are dried to a moisture content of 6 to 8% by weight, based on the total weight of the granules.

30. 10. A method for preparing one or more orally administrable dosage forms comprising the composition of any one of claims 1 to 6 held within a gel, said method comprising: vii) providing a mixture comprising starch and water; viii) heating the mixture from step i) with high shear mixing to prepare the starch for gelatinization; ix) cooling the mixture from step ii); x) combining the product of step iii) with a composition according to any one of claims 1 to 6; xi) transferring the product of step iv) into one or more molds of suitable size and shape for an orally administrable dosage form; xii) curing and drying the transferred product of step iv) to provide one or more orally administrable dosage forms comprising the composition of any one of claims 1 to 6 held within a gel.

31. 31. The method of claim 30, wherein the mixture of step i) comprises starch and water in a weight ratio of 35:65 to 55:45, preferably 40:60 to 50:50, more preferably about 45:

55.

32. 32. The method of claim 30 or claim 31, wherein the mixture of step i) further comprises one or more sweeteners.

33. 33. The method of any one of claims 30 to 32, wherein the heating in step ii) is at a temperature of 140 to 160°C under a pressure of 1 to 5 bar.

34. 34. The method of any one of claims 30 to 33, wherein said heating in step ii) is by direct steam injection.

35. 35. The method according to any one of claims 30 to 34, wherein during step iv) the product of step iii) is also combined with acidulants and / or melatonin and / or L-theanine and / or natural flavours and / or natural colours that are not encapsulated in a calcium alginate hydrogel.

36. A method according to any one of claims 30 to 34, wherein one or more of the products of step vi) are coated with a polishing agent.

37. A composition according to any one of claims 1 to 6 or an orally administrable dosage form according to any one of claims 7 to 35 for use in the treatment of a sleep disorder.

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